Xylene-diamines as antiviral agents

ABSTRACT

Compounds of the formula ##STR1## or a non-toxic acid addition salt thereof wherein R 1  is alkyl of from 1 to 20 carbon atoms; 
     R 2  is alkyl of from 12 to 20 carbon atoms; 
     R 3  is selected from the group consisting of hydrogen and hydroxyalkyl of from 2 to 8 carbon atoms; and 
     R 4  is selected from the group consisting of hydrogen, alkyl of from 1 to 8 carbon atoms and hydroxyalkyl of from 2 to 8 carbon atoms, said compounds are useful for combating viral infections in vertebrate animals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of the copending applicationSer. No. 541,240, filed Jan. 15, 1975 and now abandoned, which is inturn a divisional application of Ser. No. 330,042, filed Feb. 6, 1973and now U.S. Pat. No. 3,872,171, which is a continuation-in-part ofapplication Ser. No. 146,548, filed May 24, 1971 and since abandoned,which was in turn a continuation-in-part of application Ser. No. 62,192,filed Aug. 7, 1970 and since abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel compounds and a novel method forcombating viral infections in vertebrate animals which comprisesadministering to the animals a monoamine, a diamine or a triamine. Moreparticularly, it relates to combating viral infections in vertebrateanimals by parenteral, intranasal or topical administration of acompound of the present invention

The cells of vertebrates produce, in response to virus infection, asubstance which enables cells to resist the multiplication of a varietyof viruses. The viral-resisting or viral-interfering substances arereferred to as "interferons." They are a heterogeneous group ofantiviral proteins which vary quite widely in their molecular weights.Although such proteins may differ in their physico-chemical properties,they all exhibit the same biological properties; namely, they inhibit awide range of unrelated viruses, have no toxic or other deleteriouseffects on cells, and are species-specific (Lockart, Frontiers ofBiology, Vol. 2, "Interferons," edited by Fintner, W. B. SaunderCompany, Philadelphia, 1966, pp. 19-20).

This discovery, by Isaacs and Lindenmann, in 1957 (Proc. Roy. Soc. B.147, 258-267) gave rise to great optimism than an economic preparationof exogeneous interferon might be developed for routine clinical useagainst viral infections. However, despite great expenditures of effortand money, no safe, effective, economical source has yet been developed.An alternate approach to producing interferon has, therefore, beenpursued. This approach comprises administering to the animal to beprotected, or treated, a non-viral substance which stimulates-- orinduces--production of interferon in the cells. The interferon producedin this fashion is referred to as "endogenous" interferon.

The discovery of antiviral compounds is far more complicated anddifficult than is the discovery of antibacterial and antifungal agents.This is due, in part, to the close structural similarity of viruses andthe structures of certain essential cellular components such asribonucleic and deoxy-ribonucleic acids, and to the difficulty ofestablishing suitable tests for evaluating antiviral agents. However,despite these difficulties, numerous non-viral substances have beenfound capable of stimulating or inducing interferon formation inanimals. Included among such substances are bacteria, parasites,bacterial endotoxins, pyran copolymers, helenine, phytohemagglutinin,polyacrylic compounds, nucleic acids and polynucleotides. Use of theseinducers is, however, objected to for one or more reasons, e.g.,toxicity, antigenicity, infectiousness, and their routine clinical useappears remote (Zhdanov et al., Internat'l. Virol. I, 1st Int. Congr.Virol. Helsinki 1968, S. Karger, New York, pp. 100-1, 1969).

More recently 2,7-bis[2-(diethylamino)ethoxy]fluorene-9-onedihydrochloride, a purely synthetic material of relatively low molecularweight, has been reported to be an oral inducer of interferon in mice(Abstracts Federation Proceedings, Vol. 29, No. 2, page 635, 1970;Abstracts 2189 and 2190).

A variety of "antiviral agents" are described in the literature. Thesehave been summarized by Osdene in "Topics in Medicinal Chemistry,"edited by Rabinowitz and Myerson, Interscience Publishers, New York,1968, pages 141-171. For the purposes of his review, Osdene has made useof Herrmann's definition of "antiviral agent" (Herrmann et al., Proc.Soc. Exptl. Biol. Med. 103, 625, 1960); namely, an agent "which canproduce either a protective or therapeutic effect to the cleardetectable advantage of the virus infected host, or any material thatcan significantly enhance antibody formation, improve antibody activity,improve non-specific resistance, speed convalescence or depresssymptoms." This definition is of such breadth as to cover bothprophylactic and therapeutic agents. It includes substances such asinterferon, and a host of synthetic materials, such as 1-adamantanamine,pyrimidines, biguanides, guanidine, pteridines to mention a few. It isnoted that such synthetic materials are antiviral agents. They are notinterferon inducers but operate by a totally different mechanism.Interferon inducers may, of course, be referred to an antiviral agents.The converse, however, is not true.

Virus infections which attack animals, including man, are normallycontagious afflictions which may spread so rapidly that they can reachepidemic proportions in relatively short periods of time. In the past,many of these epidemics have resulted in large numbers of deaths andhave been responsible for huge economic losses. Obviously a method ofreducing the incidence of these viral infections, such as the method ofthis invention, would be welcome as an addition to the armamentarium ofmedical technology.

SUMMARY OF THE INVENTION

It has now been found that certain monoamines and diamines, includingheterocyclic amines having one or two nitrogen atoms in the ring, andtriamines are capable of combating viral infections in vertebrateanimals when administered by the parenteral, intranasal and topicalroutes. The compounds of this invention, many of which are novel, havethe formulae ##STR2## and the non-toxic acid addition salts thereofwherein R₁ is selected from the group consisting of alkyl of from 1 to20 carbon atoms, aralkyl, aryloxyalkyl, hydroxyalkyl of from 2 to 8carbon atoms and ##STR3## R₂ is selected from the group consisting ofalkyl of from 12 to 20 carbon atoms, aralkyl and aryloxyalkyl of from 12to 24 carbon atoms and ##STR4## R° is alkoxy of from 1 to 18 carbonatoms; each of R' and R" is selected from the group consisting ofhydrogen, alkyl and alkoxy of from 1 to 18 carbon atoms; R' and R" whentaken together are methylenedioxy;

provided that the total number of carbon atoms in R°, R' and R" is from5 to 48;

R₃ is selected from the group consisting of hydrogen, alkyl of from 1 to20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms,phenylcarbamoyloxy(lower alkyl), ω-carboxyalkanoyloxy(lower alkyl),allyl, alkanoyl of from 1 to 6 carbon atoms, alkoxy(lower alkyl),gem-di(lower alkoxy)lower alkyl, alkanoyloxy(lower alkyl), carbo(loweralkoxy)lower alkyl, and carboxy(lower alkyl);

R₄ is selected from the group consisting of hydrogen, alkyl of from 1 to8 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, carbo(loweralkoxy)lower alkyl, alkanoyloxy(lower alkyl), carboxy(lower alkyl),alkoxy(lower alkyl), phenylcarbamoyloxy(lower alkyl),ω-carboxyalkanoyloxy(lower alkyl), allyl dihydroxyalkyl of from 3 to 8carbon atoms and morpholinoethyl; with the proviso that no more than twoof the R variables are hydroxyalkyl;

R₃ and R₄ when taken together with the nitrogen to which they areattached are morpholino;

X is selected from the group consisting of straight chain alkylene offrom 2 to 6 carbon atoms and ##STR5## X' is selected from the groupconsisting of X, phenylenedimethylene, and ##STR6## m is 0 or 1, withthe provisos that only one of X and X' is ##STR7## and when X' isphenylenedimethylene, m is 0; Y is selected from the group consisting ofstraight chain alkylene of from 2 to 8 carbon atoms, andphenylenedimethylene;

A is selected from the group consisting of hydrogen, cyano, hydroxy,alkoxy of from 1 to 20 carbon atoms, alkanoyloxy of from 2 to 20 carbonatoms, phenylcarbamoyloxy, chloro, bromo, ω-carboxyalkanoyloxy(loweralkyl), alkanoyloxy of from 1 to 6 carbon atoms, carbo(lower alkoxy) andalkanoylthio of from 2 to 20 carbon atoms and alkylthio of from 1 to 20carbon atoms;

R₅ is selected from the group consisting of hydrogen, alkyl of from 1 to20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (loweralkoxy)lower alkyl and

R₆ is selected from the group consisting of hydrogen, alkyl of from 12to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (loweralkoxy)lower alkyl and ##STR8## R₇ is selected from the group consistingof alkyl of from 12 to 20 carbon atoms and ##STR9## R₈ is selected fromthe group consisting of alkyl of from 1 to 20 carbon atoms and ##STR10##each of p and n is 0 or an integer from 1 to 6, with the proviso thatthe sum of p and n is no greater than 6; and

Z is selected from the group consisting of ω-carboxy(lower alkyl),morpholino, piperidino, piperazino, N-(ω-hydroxy lower alkyl)piperazinoand N-(lower alkyl)piperazino.

Of the lower alkoxy, lower alkyl and carbo(lower alkoxy) groups, thosehaving up to four carbon atoms in the alkoxy and alkyl groups arepreferred since the starting materials are readily available. The term"phenylenedimethylene" includes, of course, the three isomeric, that is,the o--, the m-- and the p- phenylenedimethylene groups.

By "non-toxic" acid addition salts is meant those salts which arenon-toxic at the dosages administered. The non-toxic acid addition saltsof the above-mentioned bases which may be employed are the water-solubleand water-insoluble salts such as the hydrochloride, hydrobromide,phosphate, nitrate, sulfate, acetate, hexafluorophosphate, citrate,gluconate, benzoate, propionate, butyrate, sulfosalicylate, maleate,laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate(4,4'-diaminostilbene-2, 2'-disulfonate)pamoate(1,1'-methylene-bis-2-hydroxy-3-naphthoate), stearate,3-hydroxy-2-naphthoate, p-toluenesulfonate, lactate and suramin salt.

Other salts not usually regarded as non-toxic are also useful in thepractice of the present invention for instance, picrate salts which areused very infrequently in pharmaceutical applications are frequentlyused to prepare analytical samples of amine salts. These salts areuseful as intermediates in the preparation of pharmaceutical gradechemicals. They can be converted to other salts by treating the picratewith a salt whose cation forms an insoluble picrate and whose anion ispharmaceutically acceptable. A similar result may be achieved by the useof anion exchange resins.

In addition to the above compounds, compounds of formulae I and IIwherein (a) the X, X' and Y variables represent straight chain alkyleneradicals of up to 13 carbon atoms, or branchedchain alkylene groups of 3to 13 carbon atoms; (b) X, X' and Y are arylene, e.g., phenylene,naphthylene, anthrylene, biphenylene or --(CH₂)_(x) --arylene--(CH₂)_(y)-- wherein x and y are integers from 1 to 4; (c) those wherein one ormore of the R variables represent unsaturated alkyl radicals having from2 to 20 carbon atoms and from 1 to 3 double bonds; polyhydroxyalkyl;aryl (phenyl, naphthyl); aralkyl (benzyl, phenethyl, phenylpropyl);phenoxyalkyl and substituted derivatives of the aforementioned aryl,aralkyl and phenoxyalkyl wherein the substituent is in the aryl moietyand is alkyl, chloro, bromo, alkoxy or carbo (lower alkoxy); (d)compounds of formulae I and II wherein the R groups together with thenitrogen atoms to which they are attached form a heterocyclic structurewherein the heterocyclic moiety contains from 3 to 7 carbon atoms andwherein the hetero atom is at least one of N, O, or S, such asmorpholino, thiomorpholino, piperidino, piperazino, N-lower alkylpiperazino, N-(hydroxy lower alkyl)-piperazino, pyrrolo, pyrolidino,2-(lower carbalkoxy)pyrrolidino, indolo, benzimidazolo, 1-benzotriazolo,2,1,3-benzothiazole, pyrazolo, phenoxazino, azetidino; azepino,tetrazolo; an azacycloalkane such as azacylooctadecane;10,11-dihydro-5H-dibenz[b,f]azepino; a triazepino, e.g.,1,3,5-triazepino, and 11-dibenzo[1,2,5]triazepino; (e) and compounds offormula I wherein X or X' represent C=NH or C=S; (f) N-oxides of thecompounds of formulae I through IV; (g) and compounds of formula IIIwherein Z is N-substituted piperazino wherein the substituent iscarbalkoxy, acyl or --X'--NR₃ R₄ wherein X', R₃ and R₄ are as definedabove; also combat viral infections when administered to vertebrateanimals by the parenteral route.

One preferred group of compounds of Formula I includes those of thestructure ##STR11## wherein R₁ is selected from the group consisting ofalkyl of from 1 to 20 carbon atoms, aralkyl, aryloxyalkyl, and ##STR12##wherein R° is alkoxy of from 1 to 18 carbon atoms; each of R' and R" ishydrogen, alkyl or alkoxy of from 1 to 18 carbon atoms; R' and R" whentaken together are methylenedioxy;

R₂ is selected from the group consisting of alkyl of from 12 to 20carbon atoms, aralkyl, aryloxyalkyl and ##STR13## wherein R° is alkoxyof from 1 to 18 carbon atoms; each of R' and R" is hydrogen, alkyl oralkoxy of from 1 to 18 carbon atoms; R' and R" when taken together aremethylenedioxy; and R₃ and R₄ are each hydrogen;

The compounds described herein exhibit broad spectrum activity against avariety of viruses in vivo when administered parenterally(subcutaneously, intramuscularly, intraperitoneally), intranasally (e.g.by inhalation or spray) or topically to vertebrate animals. Thisusefulness is primarily one of prophylactic rather than of therapeuticcontrol of virus infections. Although the present invention is not to beconstrued as limited by such a theory, it is possible that the compoundsof this invention function in combating viral infections by virtue oftheir ability to induce the production of endogenous inerferon. They donot produce interferon in tissue culture but only in vivo and can,therefore, be considered as stimulators of host defense mechanisms.

Further, these compounds exhibit antiviral activity when administeredalone and/or in combination with an otherwise inactive, single-strandedribonucleic acid, such as highly polymerized ribonucleic acid fromyeast, yeast nucleic acid (Calbiochem 55712, Calbiochem, Los Angeles,Calif.). Those compounds which show antiviral activity when administeredalone are given at considerably lower doses when given in combinationwith the single-stranded ribonucleic acid. Particularly useful arecompounds of the structure ##STR14## wherein R₁ is alkyl of from 1 to20, and preferably 12 to 20 carbon atoms; R₂ is alkyl of from 12 to 20carbon atoms; R₃ is hydrogen, formyl, alkyl of from 1 to 20 carbon atomsor hydroxyalkyl of from 2 to 4 carbon atoms; R₄ is hydrogen orhydroxyalkyl of from 2 to 4 carbon atoms; and q is an integer from 3 to6, with the proviso that not more than two hydroxyalkyl groups arepresent; compounds of formula I wherein R₁, R₂, R₃ and R₄ are as definedimmediately above, m is 0 and X' is alkylene of from 2 to 6 carbonatoms; compounds of formula II wherein A is hydroxy; Y is straight chainalkylene of from 2 to 4 carbon atoms; and R₅ and R₆ are alkyl of from 12to 20 carbon atoms; and compounds of formula III wherein Z isN-substituted piperazino and R₇ and R₈ are each alkyl. An especiallypreferred group of compounds of formula I includes those in which R₁ andR₂ are each alkyl of from 12 to 20 carbon atoms, R₃ and R₄ are eachhydroxyethyl, X' is straight chain alkylene of from 3 to 5 carbon atoms,and m is 0. Particularly valuable are the following compounds:

N,n-dioctadecyl-N'-formyl-1,3-propanediamine,

1-dioctadecylaminomethyl-3-aminomethylbenzene,

N,n-dihexadecyl-N',N'-bis(2-hydroxyethyl)-1,4-butanediamine,

N-(2-hydroxyethyl)dioctadecylamine,

N-(3-hydroxypropyl)dioctadecylamine,

1,1-dioctadecyl-3-{2-[bis(2-hydroxyethyl)amino]ethyl}urea,

1-(N,N-dioctadecylcarbamoyl)-4-methylpiperazine,

1-(N,N-dioctadecylcarbamoyl)-4-(2-hydroxyethyl)piperazine.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention, many of which are known, are preparedby methods familiar to those skilled in the art.

U.S. Pat. No. 3,235,501, for example, discloses, in theory at least whenall combinations and permutations of the several variables areconsidered, thousands upon thousands of polyoxyalkylated aliphaticamines derived from primary and secondary mono- and diamines. Thecompounds are produced by alkoxylation (ethoxylation or propoxylation)of primary and secondary monoand diamines. In such cases, thealkoxylation reaction occur in a random manner to produce a mixture ofalkoxylated compounds in which from 1 to 25 alkylene oxide moieties maybe present. Many of the compounds of formula I above fall within thetheoretical list of compounds encompassed by this patent. However,despite the extremely broad, indeed infinite, disclosure to polyoxylatedaliphatic amines, the patent is completely devoid of reference tospecific compounds embraced by formula I above. The innumerablepossibilities of the patent disclosure coupled with the ambiguous andvague nature of the method of preparation disclosed, render it unlikelythat any specific compound would be suggested to one skilled in the art.

Also disclosed in the literature are compounds of formula III whereineach of R₇ and R₈ is hydrogen or lower alkyl (Kushner et al., J. Org.Chem. 13, 144-53, 1948; Pressman et al., J. Am. Chem. Soc. 70, 1352-8,1948). Such compounds do not induce interferon when administered toanimals as described herein. Quite unexpectedly, however, it has beenfound that when at least one of R₇ and R₈ is alkyl of twelve or morecarbon atoms, the compounds do function to combat viral infections.

The basic reaction is the alkylation or an amine, primary or secondarywith, for example, alkyl halide or hydroxyalkyl halide, usually chlorideor bromide in an organic solvent in the presence of a base or acidacceptor. Other methods of alkylation can, of course, be employed suchas the use of aluminum alkoxides, esters of sulfuric andp-toluenesulfonic acid. Appropriate methods for preparing compounds ofthe above formulae are described by Zook and Wagner, "Synthetic OrganicChemistry," John Wiley & Sons, Inc., New York, 1953, pages 666-670

Derivatives of 1,3-propanediamine are conveniently made bycyanoethylation of the appropriate primary or secondary amines byconventional methods. The propionitrile compound (R₁ R₂ NCH₂ CH₂ CN)thus obtained is then hydrogenated to the corresponding1,3-propanediamine (R₁ R₂ NCH₂ CH₂ CH₂ NH₂) by well-known methods, e.g.,hydrogenation over Raney nickel.

Acylated amines are readily prepared by treating the appropriate aminewith an acyl halide or anhydride in the presence of a base according toprocedures well known to those skilled in the art.

An alternative method for preparing compounds of formulae I and IIhaving N-hydroxyalkyl groups comprises treating a hydroxyalkyl reactant,e.g. an N,N-dialkylamino alkanol, with methane sulfonyl chloride andthen reacting the reaction mixture with the appropriatehydroxyalkylamine or di(hydroxyalkyl)amine.

Urea derivatives of formulae I and III are also prepared by conventionalmethods as by reaction of a carbamyl chloride (R₁ R₂ NCOCl) with anamino reactant H₂ N--X'--NR₃ R₄ or N-substituted piperazine in anorganic solvent in the presence of an acid acceptor which can, ofcourse, be an excess of the amine reactant.

Compounds of formula I wherein the X' variable is phenylenedimethyleneare prepared by reducing a cyanobenzylamine usually by treating it witha suitable metal hydride such as sodium dihydrobis-(2-methoxyethoxy)aluminate. These compounds may be prepared bycontacting an α-bromotolunitrile with an appropriate amine of theformula R₁ R₂ NH in dimethylacetamide in the presence of potassiumcarbonate. α-Bromotolunitriles are articles of commerce obtainable, forexample, from Shawnee Chemicals. The amine is obtained by refluxingcompound of the formula R₁ NH₂ with the appropriate carboxylic acid in asuitable solvent such as xylene and then contacting the compound formedwith sodium dihydro bis-(2-methoxyethoxy)aluminate in a suitable solventsuch as benzene to produce the desired secondary amine. Sodium dihydrobis-(2-methoxyethoxy)aluminate is an article of commerce obtainable, forexample, from Eastman Kodak Corporation under the trade name of Vitrideas a 70% solution in benzene. As will easily be recognized by thoseskilled in the art, this procedure may be employed to prepare amines inwhich R₁ and R₂ are either identical or different. If a compound inwhich R₁ and R₂ are identical is desired, a process comprising refluxingthe primary amine in a suitable solvent such as toluene in the presenceof Raney nickel catalyst to produce the desired secondary amine may alsobe employed. This process has been used infrequently because tertiaryamines which are difficult to separate from the desired product areoften formed. This problem is not encountered when compounds with largealkyl groups containing 12 to 20 carbon atoms are tested presumablybecause of the steric hindrance to tertiary amine formation afforded bythe great bulk of the alkyl moieties. The aminomethyl group of thereduced compound (--CH₂ NH₂) may then be treated, e.g., alkylated, withappropriate reactants to convert it to --CH₂ NR₃ R₄. Compounds in whichR₃ and R₄ are hydrogen are themselves useful as antiviral agents.Compounds of formula II wherein Y is phenylenedimethylene are alsoprepared by benzylation of the appropriate amine R₅ R₆ NH with acyanobenzylbromide (or chloride). The cyanobenzylamine thus produced isconverted to an ortho ester which is reduced to an acetal andsubsequently hydrolyzed to the aldehyde. Reduction of the aldehydeaffords a hydroxymethyl benzylamine. The hydroxymethyl serves asconvenient route via known procedures to formula II compounds, and alsoto formula I compounds, e.g., by halogenation and animation.

The cyanobenzyl amine may also be reduced directly with hydrogen overRaney nickel. This process is disclosed in the copending commonlyassigned application Ser. No. 498,443, filed Aug. 19, 1974 and nowabandoned. The cyanobenzylamine is first dispersed in a suitablereaction-inert solvent in a pressure vessel of suitable size andstrength. Among the usable solvents is a mixture of ethanol and hexanewherein the ratio of the volume of ethanol to the volume of hexane is inthe range of twenty to one to forty to one. The use of mixtures of otherlower alkanols and other alkanes will be obvious to those skilled in theart. The desired concentration of said cyanobenzylamine is in the rangeof 2 to 20% by weight. Ammonia in a molar amount 5 to 100 times themolar amount of said cyanobenzylamine is then introduced into thereaction medium. This may be done in a number of ways. Among these aresaturating the chilled reaction-inert solvent with ammonia gas, addingliquid ammonia directly to said chilled solvent and charging thepressure vessel with ammonia gas before charging with hydrogen gas or ina mixture with the hydrogen. Raney nickel is added to the reactionmedium containing the cyanobenzylamine. The weight ratio of Raney nickelused to said cyanobenzylamine is in the range of 0.05 to 5.0 with thepreferred ratio ranging from 0.5 to 2.5. The W2 variety of Raney nickelin either a water or benzene slurry is preferred. The pressure vessel isthen charged with hydrogen gas to a pressure between about 10 and 100psig. with a preferred range of about 45 to 55 psig. and the pressure ismaintained at a substantially constant value throughout the course ofthe reaction by adding hydrogen as needed. The pressure vessel isagitated and the reaction proceeds at temperatures between about 0° and50° C. and preferably between about 15° and 30° C. until the reaction issubstantially complete. The product may be recovered from the reactionmixture by filtering the Raney nickel, washing with ethanol, adding thewash to the filtrate and concentrating the filtrate to an oil by meansof vacuum distillation. The oil is then dissolved in methylene chloride,washed with water and saturated sodium chloride, dried over magnesiumsulfate and concentrated by vacuum distillation to the desired productin substantially pure form.

The herein-described compounds of formulae I, II and III wherein the R₁,R₂, R₅, R₆, R₇ or R₈ groups are substituted benzyl ##STR15## areconveniently produced from appropriate benzaldehydes via reduction to abenzyl alcohol followed by conversion to a benzyl chloride and thenanimation. Alternatively, the benzaldehyde is reductively aminated toproduce, depending upon the conditions, a mono- or dibenzylamine.Utilization of the benzylamine derivatives in conventional reactions asdescribed above affords compounds of formulae I-III.

Acid addition salts of the compounds described herein are prepared byconventional procedures as by mixing the amine compound in a suitablesolvent with the required acid and recovering the salt by evaporation orby precipitation by addition of a non-solvent for the salt.Hydrochloride salts are readily prepared by passing dry hydrogenchloride through a solution of the amine compound in an organic solventsuch as ether.

The antiviral activity of the above-described materials is determined bythe following procedures. In the first procedure, the test compound isadministered to mice by the intraperitoneal route eighteen totwenty-four hours prior to challenging the mice with a lethal dose ofencephalomyocarditis virus and determining the survival rate ten daysafter challenge. The procedure in which the drug is given eighteen totwenty-four hours before and at a distinctly different site from virusinjection is designed to eliminate local effects between drug and virusand select only compounds which produce a systemic interferon response.

The second general procedure discriminates between compounds whichexhibit antiviral activity in the first procedure for their ability toproduce an antiviral state in mice as indicated by their ability tostimulate circulating interferon after parenteral administration. Inboth procedures, the test compounds are administered alone and incombination with from about 2 to about 20 times by weight of anotherwise inactive (non-inducer of interferon and non-antiviral),single-stranded, highlypolymerized ribonucleic acid from yeast, yeastnucleic acid.

Parenteral, topical and intranasal administration of the above-describedamines to an animal, including man, before exposure of the animal to aninfectious virus provide rapid resistance to the virus. The resistanceengendered is nonspecific and is effective against a great number ofviruses. Such administration is effective when given as much as fivedays prior to exposure to the virus. Preferably, however, administrationshould take place from about three days to about one day before exposureto the virus, although this will vary somewhat with the particularanimal species and the particular infectious virus.

When administered parenterally the materials of this invention are usedat a level of from about 1 mg./kg. of body weight to about 250 mg./kg.of body weight. The favored range is from about 5 mg./kg. to about 100mg./kg. of body weight, and the preferred range from about 5 mg./kg. toabout 50 mg./kg. of body weight. The dosage, of course, is dependentupon the animal being treated and the particular amine compound involvedand is to be determined by the individual responsible for itsadministration. Generally, small doses will be administered intiallywith gradual increase in dosage until the optimal dosage level isdetermined for the particular subject under treatment.

Intraperitoneal injections are the preferred method of parenteralinjection for several reasons: simplicity, convenience and the compoundsappear less toxic. Vehicles suitable for parenteral injection may beeither aqueous such as water, isotonic saline, isotonic dextrose,Ringer's solution, or nonaqueous such as fatty oils of vegetable origin(cottonseed, peanut oil, corn, sesame) and other non-aqueous vehicleswhich will not interfere with the efficacy of the preparation and arenon-toxic in the volume or proportion used (glycerol, ethanol, propyleneglycol, sorbitol). Additionally, compositions suitable forextemporaenous preparation of solutions prior to administration mayadvantageously be made. Such compositions may include liquid diluents,for example, propylene glycol, diethyl carbonate, glycerol, sorbitol.

When the materials of this invention are administered, they are mosteasily and economically used in a dispersed form in an acceptablecarrier. When it is said that this material is dispersed, it means thatthe particles may be molecular in size and held in true solution in asuitable solvent or that the particles may be colloidal in size anddispersed through a liquid phase in the form of a suspension or anemulsion. The term "dispersed" also means that the particles may bemixed with and spread throughout a solid carrier so that the mixture isin the form of a powder or dust. This term is also meant to encompassmixtures which are suitable for use as sprays, including solutions,suspensions or emulsions of the agents of this invention.

In practicing the intranasal route of administration of this inventionany practical method can be used to contact the inducer with therespiratory tract of the animal. Effective methods includeadministration of the inducer by intranasal or nasopharyngeal drops andby inhalation as delivered by a nebulizer or an aerosol. Such methods ofadministration are of practical importance because they provide an easy,safe and efficient method of practicing this invention. For intranasaladministration of the inducer, usually in an acceptable carrier, aconcentration inducer between 1.0 mg./ml. and 100 mg./ml. issatisfactory. Concentrations in the range of about 30 to 50 mg./ml.allow administration of a convenient volume of material.

For topical application the inducers are most conveniently used in anacceptable carrier to permit ease and control of absorption. Here alsoconcentrations in the range of from about 1.0 mg./ml. to about 250mg./ml. are satisfactory. In general, in the above two methods ofadministration a dose within the range of about 1.0 mg./kg. to about 250mg./kg. of body weight and, preferably, from about 5.0 mg./kg. to about50 mg./kg. of body weight will be administered.

The compounds employed in this invention may be employed along, i.e.,without medicinals, as mixtures of more than one of the herein-describedcompounds or in combination with other medicinal agents, such asanalgesics, anesthetics, antiseptics, decongestants, antibiotics,vaccines, buffering agents and inorganic salts, to afford desirablepharmacological properties. Further, they may be administered incombination with hyaluronidase to avoid or, at least, to minimize localirritation and to increase the rate of absorption of the compound.Hyaluronidase levels of at least about 150 (U.S.P.) units are effectivein this respect although higher or lower levels can, of course, be used.

Those materials of this invention which are water-insoluble, includingthose which are of low and/or difficult solubility in water, are, foroptimum results, administered in formulations, e.g., suspensions,emulsions, which permit formation of particle sizes of less than about20μ. The particle sizes of the formulations influence their biologicalactivity apparently through better absorption of the active materials.In formulating these materials various surface active agents andprotective colloids are used. Suitable surface active agents are thepartial esters of common fatty acids, such as lauric, oleic, stearic,with hexitol anhydrides derived from sorbitol, and the polyoxyethylenederivatives of such ester products. Such products are sold under thetrademarks "Spans" and "Tweens," respectively, and are available fromthe Atlas Powder Co., Wilmington, Delaware. Cellulose ethers, especiallycellulose methyl ether (Methocel, available from the Dow Chemical Co.,Midland, Mich.) are highly efficient as protective colloids for use inemulsions containing the materials of this invention.

The water-soluble materials described herein are administered foroptimum results in aqueous solution.

The production of interferon by the administration of compoundsdescribed herein is demonstrated by the protection of animals, generallymice as the initial test animal, against viral infections.Encephalomyocarditis virus is a convenient test organism. The challengevirus is prepared by inoculating mice for at least five passages with aneurotropic strain of encephalomyocarditis virus (infected mouse brain).A 10 percent suspension of infected brain tissue is prepared frominfected mice and stored at -70° C. until needed (Takano et al., J.Bact. 90, 1542, 1965). It is titrated to a dose which will cause deathin five to seven days after challenge to unprotected animals. It isgiven subcutaneously into the neck scruff. The appropriate dose iscontained in 0.1 ml. In general, the dose administered to the animals isfrom 10 to 25 times the LD₅₀ (the dose which causes the death of 50percent of the animals).

For determination of antiviral activity, mice are parenterally(intraperitoneally) injected with the test compound at levels of 5 or 10mg./kg. and 50 mg./kg. of body weight eighteen to twenty hours prior tovirus challenge and the number of survivors determined ten days afterchallenge. Interferon production is monitored following injection of thetest compound according to the procedure described by Wheelock, Proc.Soc. Exptl. Biol. Med. 124, 855-85 (1967).

Once interferon induction by a given compound is observed, the compoundis administered to the test animal at various time intervals prior tochallenge, e.g., 6, 36, 48 and 72 hours, and by other parenteral routes,e.g., intramuscular and subcutaneous.

The induction of interferon is demonstrated in the following manner. Arepresentative formulation containingN,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine as theinducer is exemplified.

A mixture of the inducer (100 mg.) and polysorbate 80 (Tween 80; 0.1ml.) is heated in a boiling water bath. The amine melts and iscompletely miscible with the polysorbate 80. To this mixture is thenadded with vigorous vortexing 2.5 ml. of the following compositionpreviously warmed to about 55° C.:

    ______________________________________                                        Methocel-15 (Dow Chemical Co.)                                                                        0.50 g.                                               Tween 80                1.00 g.                                               CMC-70*                 10.00 g.                                              Sodium chloride         9.00 g.                                               Distilled water         984.80 g.                                             ______________________________________                                         *Sodium carboxymethyl cellulose available from Hercules Powder Co.,           Wilmington, Delaware.                                                    

Then 7.28 ml. of a 0.14M sodium chloride-0.01M sodium phosphate solutionof pH 7.0 warmed at 55° C. is added with continued vigorous vortexing.The formulation thus produced contains 10 mg. of the antiviral agent perml. of suspension.

The hydrochloride salt ofN,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)1,3-propanediamine is readilyformulated by vigorous vortexing of the salt in hot 0.14 M sodiumchloride -0.01 M sodium phosphate of pH 7.0.

Interferon induction is determined using female albino Swiss mice(Charles-River) as the test animal. Mice weighing 20 to 25 grams arehoused in groups of five and are given food and water ad libitum. Thetest material is evaluated at 5 mg./kg. of body weight and given in asingle intraperitoneal injection (0.5 ml.) eighteen to twenty hoursprior to bleeding. The mice are bled under ether anesthesia from thebracheal artery, the blood collected in heparinized pipettes and tubes,and the pooled plasma from the five mice prepared by centrifugation ofthe blood for thirty minutes at 2,000 RPM. Dilutions of the plasma arepipetted into plastic tubes containing sheets of L-929 mouse fibroblasts(available from Flow Laboratories, Rockville, Maryland). These latterare twenty-four hour cultures in L-15 media containing 10 percent fetalcalf serum and antibiotics (available from Grand Island BiologicalCompany, Grand Island, New York). The cultures are grown from initialplantings of 1 ml. of 100,000 cells/ml. After twenty-four hours ofincubation with the plasma, the cultures are washed with media andchallenged with 0.2 ml. of a dilution of vesicular stomatitis virustitrated to produce a complete destruction of the cell sheets intwenty-four to forty-eight hours. The cultures are in contact with thevirus dilution in protein-free media for one hour to allow the virus toadsorb to the cells and then the tubes receive 1 ml. of complete media.After twenty-four to forty-eight hours of incubation at 37° C., thetubes are scored for cytopathogenic effect of the virus and comparedwith standard interferon samples. Interferon units are recorded as thereciprocal of the plasma concentration which affords 50 percentprotection to the cell sheets.

The antiviral activity ofN,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)1,3-propanediamine isdetermined using female albino Swiss mice (Charles-River) as the testanimal. MIce weighing 20 to 25 grams are housed in groups of five andare given food and water ad libitum. The test material is evaluated attwo dose levels (5 mg./kg. and 50 mg./kg. of body weight) andadministered in a single 0.5 ml. intraperitoneal injection eighteen totwenty hours prior to virus challenge. On the following day (eighteen totwenty hours post injection) the mice are challenged subcutaneously withan 0.2 ml. injection of encephalomyocarditis virus at a dilutiontitrated to give a five- to six-day death endpoint in unprotectedanimals. Survival data is recorded for the subsequent ten days and theten-day survival is used as an index of efficacy. Validity of each testis established by the inclusion of unprotected groups and groupsreceiving pyran co-polymer, 100 mg./kg., for positive control.

The water-soluble compounds of the invention are convenientlyadministered in phosphate buffered saline. The water-insoluble compoundsare administered in formulations as previously noted. Dimethylsulfoxideserves as a suitable vehicle for water-insoluble compounds. Arepresentative formulation for such compounds comprises 25 to 100 mg. ofthe chosen drug, dimethylsulfoxide (1 ml.), polysorbate 80 (1 ml.) and 8ml. of a composition comprising:

    ______________________________________                                        Methocel-15             0.50 g./l.                                            Polysorbate 80          1.00 g./l.                                            CMC-70                  10.00 g./l.                                           Sodium chloride         9.00 g./l.                                            Methyl p-hydroxybenzoate                                                                              1.80 g./l.                                            Propyl p-hydroxybenzoate                                                                              0.20 g./l.                                            Distilled water         984.00 g./l.                                          ______________________________________                                    

In certain instances, as where clumping of the drug particles occurs,sonication is employed to provide a homogeneous system.

To administer the above-mentioned ribonucleic acid in combination withthe antiviral agent, the RNA is dissolved in phosphate buffered salinesolution at a concentration of 10 mg./ml. For administration to mice,the antiviral agent was dissolved in a suitable carrier, phosphatebuffered saline for water-soluble materials or one of theabove-mentioned vehicles for water-insoluble compounds, atconcentrations of 1 mg. and 5 mg./ml. Equal volumes of the RNA andantiviral agent solutions were mixed and approximately 0.5 ml. wasadministered by a parenteral route to the mice. Under these conditions,the dosage levels were approximately 100 μ g./kg. RNA and either 50 μg.or 10 μg./kg. antiviral agent.

EXAMPLE I N,N-Dioctadecyl-N',N'-Bis(2-Hydroxyethyl)-1,3-Propanediamine

A mixture of octadecylbromide (666 g., 2.0 moles),N-(3-aminopropyl)-diethanolamine (162 g., 1.0 mole) and potassiumcarbonate (276 g., 2.0 moles) is stirred vigorously and heated slowly to120° C. and held at this temperature for one-half hour. The mixture isallowed to cool to 70° C. then 500 ml. of a 1:1 methylene chloride-watermixture added. The mixture is then slowly poured into a stirred mixtureof methylene chloride (9.75 liters)-water (9.75 liters). The methylenechloride phase is separated after fifteen minutes and the remainingaqueous phase extracted with methylene chloride (4 liters). The combinedmethylene chloride extracts are dried over anhydrous magnesium sulfatethen stripped to one-half volume under reduced pressure. The concentrateis then stirred with silicic acid (300 g.) for one-half hour, thesilicic acid removed and the clear solution slowly poured into acetone(16 liters) containing succinic acid (300 g.). The mixture is cooledslowly to 10° C. and the succinate salt filtered off; 615 g. (68 percentof theory); m.p. 78°-90° C.

It is purified by recrystallization from acetone-methylene chloride(2-1).

The free base is obtained by dissolving the succinate salt (420 g.) inmethylene chloride (4 liters) and aqueous sodium hydroxide (2.5 litersof 5 percent solution). The mixture is stirred for fifteen minutes, themethylene chloride phase separated and washed successively with aqueoussodium hydroxide (1× 18 liters of 5 percent solution), water (3× 6liters) and saturated aqueous sodium chloride (1× 6 liters). It is thendried (MgSO₄), filtered and evaporated in vacuo to an oil. The oil isdissolved in acetone (5 liters) at 50° C. and the solution allowed tocool slowly to give a white precipitate (267 g.) m.p. 39°-41° C. Anotherpreparation yielded a somewhat lower melting point of 36-36.8° C.

Additional product (20 g.) is obtained by cooling the filtrate to 0° C.Total yield is 287 g.; 43 percent of theory.

    ______________________________________                                        Elemental analysis                                                            Theory for C.sub.43 H.sub.90 N.sub.2 O.sub.2                                                          Found:                                                ______________________________________                                        C      77.41                    C   77.42                                     H      13.60                    H   13.84                                     N      4.20                     N   4.16                                      ______________________________________                                    

Potentiometric Titration

Solvent: acetic acid

Titrant: 0.5 N perchloric acid in acetic acid

Theory= 333.6; Found= 342.0

Infra-red (1% in KBr)

Major absorption maxima (in microns) at:

3.05, 3.43, 3.52, 6.80, 7.15, 7.25, 7.65, 8.32, 8.39, 8.68, 9.15, 9.24,9.30, 9.62, 9.70, 11.04, 13.96.

The dilactate salt is prepared by adding two equivalents of lactic aciddissolved in ether to an ether solution of the base, followed byevaporation of the ether; m.p. 50°-52° C. becomes tacky and melts at60°-62° C.

The diphosphate salt is prepared by adding excess phosphoric acid to asolution of the base in hexane. It is recrystallized from a large volumeof methanol; m.p. becomes a gel at 140° C.; brown at 175°-190° C. andmelts at 245°-247° C.

The dihydrochloride salt is prepared by bubbling dry hydrogen calorideinto an ether solution of the base. The residue obtained by removal ofthe ether is slurried in acetone, filtered, and recrystallized fromether containing some methanol; m.p. gels at 180°-182° C. and meltscompletely at 238°-240° C.

EXAMPLE II N,N-Dioctadecyl-N',N'-Bis(2-Hydroxyethyl)Ethanediamine

A mixture of octadecylbromide (6.66 g., 0.02 mole),N-(2-aminoethyl)diethanolamine (1.48 g., 0.01 mole) and potassiumcarbonate (2.76 g., 0.02 mole) is heated at reflux under an atmosphereof nitrogen for two hours. The reaction mixture is then cooled andtreated with aqueous sodium hydroxide (50 ml. of 10 percent solution).Ethyl acetate (50 ml.) is added, the mixture thoroughly agitated and theethylacetate separated, washed with water, and dried over anhydrousmagnesium sulfate. Removal of the solvent by evaporation affords thecrude product which is recrystallized from ethylacetate or acetone; m.p.33°-34° C.

The hydrochloride, phosphate, succinate and picrate salts are made byadding the above base to ethylacetate containing stochiometric amountsof the respective acids. The salts are recovered by filtration, washedwith cold ethylacetate, and dried.

    ______________________________________                                        Salt               M.P. (° C.)                                         ______________________________________                                        dihydrochloride     228-30                                                    diphosphate         102-3                                                     disuccinate         155-6                                                     dipicrate           84-6                                                      ______________________________________                                    

Repetition of the above procedure but using the appropriate(2-hydroxyalkyl)alkanediamine derivative and the appropriate alkylbromide produces the following compounds:

    __________________________________________________________________________     ##STR16##                                                                    R.sub.1  R.sub.2                                                                              R.sub.3       R.sub.4 n  Salt  M.P. (° C.)             __________________________________________________________________________    C.sub.16 H.sub.33                                                                     C.sub.16 H.sub.33                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   2 2H.sub.3 PO.sub.4                                                                    133-5                          CH.sub.2 CH.sub.2 OH                                                                  C.sub.18 H.sub.37                                                                    C.sub.18 H.sub.37                                                                           CH.sub.2 CH.sub.2 OH                                                                   2 2HBr   236-8                          C.sub.20 H.sub.41                                                                     C.sub.20 H.sub.41                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 O                                                                    3 --     38-45                          C.sub.20 H.sub.41                                                                     C.sub.20 H.sub.41                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   2 2HCl   188-9                          C.sub.20 H.sub.41                                                                     C.sub.20 H.sub.41                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   2 2H.sub.3 PO.sub.4                                                                    220-3                          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   4 --     51-2                           C.sub.16 H.sub.33                                                                     C.sub.16 H.sub.33                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   4 --     44-5                           C.sub.14 H.sub.29                                                                     C.sub.14 H.sub.29                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   4 --     39                             C.sub.16 H.sub.33                                                                     C.sub.16 H.sub.33                                                                    CH.sub.2 CH.sub.2OCH.sub.2 CH.sub.2                                                                  3 2HCl   167-170                        C.sub.14 H.sub.29                                                                     C.sub.14 H.sub.29                                                                    CH.sub.2 CH.sub.2OCH.sub.2 CH.sub.2                                                                  3 2HCl   174-7                          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                    CH.sub.2 CH.sub.2OCH.sub.2 CH.sub.2                                                                  3 2HCl   170-1                          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   5 --     32-3                           C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                    CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OH                                                                   6 --     49-50                          __________________________________________________________________________

example iii n,n-dioctadecyl-1,3-Propanediamine

A. A two-gallon autoclave is charged with3-(dioctadecylamino)propionitrile (100 g.), ethanol (3750 ml.)containing anhydrous ammonia (100 g.) and Raney nickel (20 g. dry basis)and purged with nitrogen, then with hydrogen. It is then sealed and thehydrogen pressure raised to 250 psi. The autoclave is agitated, thetemperature raised to 70° C. and the mixture held at this temperaturefor 1.5 hours at which time hydrogen absorption has ceased. Theautoclave is cooled to 20° C., vented, and the contents removed. Thecatalyst is filtered off, washed with ethanol, and the combined washingsand reaction mixture concentrated in vacuo to a viscous green-yellow oil(82 g.) which solidified upon standing; m.p. 39°-41° C.

Analysis: Calc'd. for C₃₉ H₈₂ N₂ : C, 80.97; H, 14.17; N, 4.44 percentFound: C, 80.60; H, 14.17; N, 4.79 percent.

3-(Dioctadecylamino)propionitrile is prepared by refluxing a mixture ofdioctadecylamine (200 g.) and acrylonitrile (1903.8 ml.) for eighteenhours. The mixture is then concentrated to a waxy semi-solid which isslurried in acetone, filtered, and air dried overnight.

B. The monoacyl derivatives of N,N-dioctadecyl-1,3-propanediamine areprepared as follows:

To a solution of methylene chloride (500 ml. per 0.1 mole of reactants)containing equimolar amounts of N,N-dioctadecyl-1,3-propanediamine andtriethylamine and cooled in an ice-bath is added an equimolar amount ofthe appropriate acyl chloride in methylene chloride (25 ml. per 0.1 moleof acyl chloride) over a period of fifteen minutes. The mixture isstirred for ten minutes then brought to room temperature and stirred forone hour. The methylene chloride phase is separated and extracted withwater (3× 25 ml.). The water extract is in turn extracted with methylenechloride (2× 25 ml.) and the combined methylene chloride phases dried(Na₂ SO₄) then evaporated under reduced pressure. The residue is takenup in benzene and the solution passed through a silica gel column. Thecolumn is eluted with benzene, then with benzene containing increasingamounts of ethyl acetate; e.g., 5, 10, 25, and 50 percent. The eluate issubjected to thin layer chromatography (ethyl acetate) and thosefractions which show only one spot, combined and evaporated.

The following are thus prepared:

N-acetyl derivative M.P. 50°-52° C.

N-propionyl derivative M.P. 48.5°-49° C.

In like manner, the following compounds are prepared from appropriatereactants:

    ______________________________________                                         ##STR17##                                                                    R.sub.1        R.sub.2     R.sub.3 '                                          ______________________________________                                        C.sub.18 H.sub.37                                                                           C.sub.18 H.sub.37                                                                          C.sub.3 H.sub.7                                    C.sub.18 H.sub.37                                                                           C.sub.18 H.sub.37                                                                          C.sub.5 H.sub.11                                   C.sub.16 H.sub.33                                                                           C.sub.16 H.sub.33                                                                          H                                                  C.sub.16 H.sub.33                                                                           C.sub.16 H.sub.33                                                                          CH.sub.3                                           CH.sub.3      C.sub.12 H.sub.25                                                                          C.sub.2 H.sub.5                                    CH.sub.3      C.sub.12 H.sub.25                                                                          H                                                  ______________________________________                                    

c. formyl derivatives are prepared as follows:

N,N-dioctadecyl-N'-formyl-1,3-propanediamine

A mixture of N,N-dioctadecyl-1,3-propanediamine (4.88 g.), ethanol (15ml.) and methyl formate (35 ml.) is heated at reflux for one-half four.By-product methanol is distilled off and additional methyl formate (20ml.) added. The mixture is refluxed for a half hour and allowed to standovernight. It is taken to dryness under reduced pressure and the whitesolid residue recrystallized from ethyl acetate, Yield= quantitative:m.p. 42°-46° C.

EXAMPLE IV N-(2-Hydroxyethyl)-N',N'-Dioctadecyl-1,3-Propanediamine

To a stirred solution of N,N-dioctadecyl-3-aminopropanol (1.16 g., 2mM.) in chloroform (30 ml.) is added methanesulfonyl chloride (0.285 g.,2.5 mM.) and the mixture stirred for seventy-five minutes. Ethanoloamine(1.22 g., 20 mM.) is added and the mixture refluxed for forty-fiveminutes, then cooled and diluted with chloroform (200 ml.). Thechloroform solution is washed successively with aqueous sodium hydroxide(5 percent), water and saturated aqueous sodium chloride. It is thendried (Na₂ SO₄) and concentrated to a waxy solid.

Picrate Salt: The free base is dissolved in ethanol (100 ml.) and asolution of picric acid (2 g.) in ethanol (20 ml.) added. The saltprecipitates upon chilling the solution. It is filtered off, washed withcold ethanol and dried, 1.2 g., m.p. 149°-151° C. Recrystallization fromhot ethanol raises the melting point to 150°-152° C.

In like manner, the following compounds are prepared using appropriatereactants (HNR₃ R₄) in place of ethanolamine. The hydrochloride saltsare prepared by bubbling excess dry hydrogen chloride gas into achloroform solution of the free base and the salt recovered byevaporation of the solvent.

    __________________________________________________________________________     ##STR18##                                                                    R.sub.3   R.sub.4       Salt  M.P. (° C.)                              __________________________________________________________________________    H       CH.sub.2 CH.sub.2 CH.sub.2 OH                                                                 picrate                                                                             121-2                                           H       CH.sub.2 CH(OH)CH.sub.2 OH                                                                    picrate                                                                             39-41                                           H       n-C.sub.3 H.sub.7                                                                             picrate                                                                             64-6                                            H       n-C.sub.6 H.sub.13                                                                            HCl   119-22                                          H       n-C.sub.7 H.sub.15                                                                            HCl   53-7                                            H       CH.sub.2 CH.sub.2 OCH.sub.3                                                                   HCl   96-9                                            H       CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                            HCl   90-4                                            H       CH.sub.2 CH(OCH.sub.3).sub.2                                                                  HCl   83-8                                            H       (CH.sub.2).sub.3 N(CH.sub.2 CH.sub.2 OH).sub.2                                                picrate                                                                             116-8                                           H       (CH.sub.2).sub.3 NH(CH.sub.2 CHOHCH.sub.3)                                                    picrate                                                                             105-10                                          H       CH.sub.2 CHOHCH.sub.2 N(C.sub.2 H.sub.5).sub.2                                                HCl   115-7                                           C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5 picrate                                                                             108-10                                          n-C.sub.4 H.sub.9                                                                     n-C.sub.4 H.sub.9                                                                             picrate                                                                             66-7                                            CH.sub.3                                                                              CH.sub.2 CH.sub.2 OH                                                                          picrate                                                                             80-2                                            n-C.sub.4 H.sub.9                                                                     CH.sub.2 CH.sub.2 OH                                                                          picrate                                                                             48-52                                           CH.sub.2 CHOHCH.sub.3                                                                 CH.sub.2 CHOHCH.sub.3                                                                         --    (an oil)                                        CH.sub.2 CHOHCH.sub.3                                                                 CH.sub.2 CHOHCH.sub.3                                                                         HCl   52-4; 98-101                                    H       CH.sub.2 CH.sub.2 -morpholino                                                                 --    55-67, 90                                       H       CH.sub.2 CH.sub.2 -morpholino                                                                 HCl   137                                             H       CH(CH.sub.3)CH.sub.2 COOC.sub.2 H.sub.5                                                       HCl   56-79                                           H       (CH.sub.2).sub.4OH                                                                            --    34-34.5                                         H       (CH.sub.2).sub.4OH                                                                            picrate                                                                             84-6; 94                                        H       (CH.sub.2).sub.5OH                                                                            --    35-6                                            H       (CH.sub.2).sub.5OH                                                                            picrate                                                                             65-70; 85-90                                    C.sub.2 H.sub.5                                                                       CH.sub.2 CH.sub.2 OH                                                                          picrate                                                                             80-6                                            CH.sub.3                                                                              (CH.sub.2).sub.4OH                                                                            --    91-4                                            CH.sub.2 COOH                                                                         CH.sub.2 COOH   --    75-90                                           CH.sub.2 COOCH.sub.3                                                                  CH.sub.2 COOCH.sub.3                                                                          --    75-7                                            (CH.sub.2).sub.3 OH                                                                   (CH.sub.2).sub.3 OH                                                                           --    41-3                                            (CH.sub.2).sub.3 OH                                                                   (CH.sub.2).sub.3 OH                                                                           picrate                                                                             91-5; 100-5                                     __________________________________________________________________________

EXAMPLE V N,N-Dioctadecyl-N',N'-Diallyl-1,3-Propanediamine

A slurry of N,N-dioctadecyl-1,3-propanediamine (2.895 g., 5 mM.), allylbromide (4.3 ml., 50 mM.), potassium carbonate (2.0 g.) and methylenechloride (10 ml.) is stirred at room temperature for three hours. Themixture is then cooled in an ice-bath, filtered, and the filtratechromatographed on acid-washed silica gel. The product is eluted with 5percent methanol-95 percent ethylacetate and the free base recovered byevaporation of the solvent.

The picrate salt, prepared according to the procedure of Example IV,melts at 86°-88° C.

Repetition of this procedure but substituting methyl bromoacetate forallyl bromide producesN,N-dioctadecyl-N',N'-bis(carbomethoxymethyl)-1,3-propanediamine. Itshydrochloride, prepared by the procedure of Example IV, melts at 75°-77°C.

The following compounds are similarly prepared from appropriatereactants:

    ______________________________________                                         ##STR19##                                                                    R.sub.1   R.sub.2     R.sub.3        n                                        ______________________________________                                        C.sub.16 H.sub.33                                                                      C.sub.16 H.sub.33                                                                         CH.sub.2CHCH.sub.2                                                                            2                                        C.sub.20 H.sub.41                                                                      C.sub.20 H.sub.41                                                                         CH.sub.2CHCH.sub.2                                                                            3                                        CH.sub.3 C.sub.16 H.sub.33                                                                         CH.sub.2CHCH.sub.2                                                                            2                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                         CH.sub.2CHCH.sub.2                                                                            6                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                         n-C.sub.3 H.sub.7                                                                             3                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                         CH.sub.2 CH.sub.2 OCH.sub.3                                                                   3                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                         CH.sub.2 CH.sub.2 -morpholino                                                                 3                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                         CH.sub.2 CH(OCH.sub.3).sub.2                                                                  3                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                         CH.sub.2 CH.sub.2 OCOCH.sub.3                                                                 3                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                         CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5                                                        3                                        ______________________________________                                    

example vi n,n-bis(2-Hydroxyethyl)-N'-Octadecyl-1,3-Propanediamine

A solution of octadecyl bromide (26.65 g., 80 mM.),N-(3-aminopropyl)diethanolamine (105 g., 640 mM.) and benzyl alcohol(120 ml.) is heated at 130° C. for twenty-three hours. The benzylalcohol is removed in vacuo (0.1 mm. Hg, and 75° C.) and the residuetaken up in methylene chloride (250 ml.). The methylene chloridesolution is washed with aqueous sodium hydroxide (1 N) then with brine.It is dried (Na₂ SO₄), concentrated, and distilled; b.p. 242°-246° C. at0.1 mm Hg. The product is a waxy solid.

EXAMPLE VIIN,N-Bis(2-Hydroxyethyl)-N'-(n-Butyl)-N'-Octadecyl-1,3-Propanediamine

A mixture of N,N-bis(2-hydroxyethyl)-N'-octadecyl-1,3-propanediamine(500 mg., 1.2 mM.), n-butyl bromide (164 mg., 1.2 mM.) and potassiumcarbonate (160 mg., 1.2 mM.) is heated at 100° C. for two hours then at130° C. for two more hours. The mixture is cooled, taken up inchloroform (100 ml.) and the chloroform solution washed successivelywith 5 percent aqueous sodium hydroxide (100 ml.), water and brine, thendried (Na₂ SO₄). Removal of the chloroform provides the free base (540mg.).

The picrate salt, prepared by the procedure of Example IV, melts at85°-87° C.

In like manner,N,N-bis(2-hydroxyethyl)-N'-(n-propyl)-N'-octadecyl-1,3-propanediamine isprepared from n-propylbromide. Its picrate salt melts at 105°-106° C.

The following compounds and their picrate salts are prepared in likemanner by alkylation of the products of Examples IV and VI with theappropriate reactant:

    ______________________________________                                         ##STR20##                                                                    R.sub.3     R.sub.4     R.sub.2 R.sub.1  n                                    ______________________________________                                        CH.sub.2 CH.sub.2 OH                                                                     CH.sub.2 CH.sub.2 OH                                                                       C.sub.18 H.sub.37                                                                     C.sub.12 H.sub.25                                                                      6                                    (CH.sub.2).sub.4 OH                                                                      (CH.sub.2).sub.4 OH                                                                        C.sub.18 H.sub.37                                                                     CH.sub.3 3                                    (CH.sub.2).sub.4 OH                                                                      (CH.sub.2).sub.4 OH                                                                        C.sub.18 H.sub.37                                                                     C.sub.6 H.sub.13                                                                       3                                    (CH.sub.2).sub.4 OH                                                                      (CH.sub.2).sub.4 OH                                                                        C.sub.18 H.sub.37                                                                     CH.sub.3 6                                    (CH.sub.2).sub.4 OH                                                                      (CH.sub.2).sub.4 OH                                                                        C.sub.18 H.sub.37                                                                     C.sub.8 H.sub.17                                                                       6                                    (CH.sub.2).sub.8 OH                                                                      (CH.sub.2).sub.8 OH                                                                        C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                      3                                    (CH.sub.2).sub.8 OH                                                                      (CH.sub.2).sub.8 OH                                                                        C.sub.18 H.sub.37                                                                     n-C.sub.4 H.sub.9                                                                      3                                    (CH.sub.2).sub.8 OH                                                                      (CH.sub.2).sub.8 OH                                                                        C.sub.18 H.sub.37                                                                     C.sub.16 H.sub.33                                                                      5                                    CH.sub.2 CH.sub.2 CH.sub.2 OH                                                            CH.sub.2 CH.sub.2 CH.sub.2 OH                                                              C.sub.16 H.sub.33                                                                     CH.sub.3 2                                    CH.sub.2 CH.sub.2 CH.sub.2 OH                                                            CH.sub.2 CH.sub.2 CH.sub.2 OH                                                              C.sub.18 H.sub.37                                                                     CH.sub.3 5                                    (CH.sub.2).sub.6 OH                                                                      (CH.sub.2).sub.6 OH                                                                        C.sub.18 H.sub.37                                                                      ##STR21##                                                                             2                                    (CH.sub.2).sub.6 OH                                                                      (CH.sub.2).sub.6 OH                                                                        C.sub.18 H.sub.37                                                                      ##STR22##                                                                             5                                    CH.sub.2 CH.sub.2 OH                                                                     CH.sub.2 CH.sub.2 OH                                                                       C.sub.20 H.sub.41                                                                     C.sub.6 H.sub.5 CH.sub.2                                                               3                                    CH.sub.2 CH.sub.2 OH                                                                     CH.sub.2 CH.sub.2 OH                                                                       C.sub.12 H.sub.25                                                                     C.sub.6 H.sub.5 OCH.sub.2                                                              3                                    CH.sub.2 CH.sub.2 OH                                                                     CH.sub.2 CH.sub.2 OH                                                                       C.sub.16 H.sub.33                                                                     C.sub.6 H.sub.5 OCH.sub.2                                                              6                                    CH.sub.2 CH(OH)CH.sub.3                                                                  CH.sub.2 CH(OH)CH.sub.3                                                                    C.sub.14 H.sub.29                                                                     C.sub.6 H.sub.5 OCH.sub.2                                                              5                                    CH.sub.2 CH.sub.2 OH                                                                     CH.sub.2 CH.sub.2 OH                                                                       C.sub.18 H.sub.37                                                                     CH.sub.2 CH.sub.2 OCH.sub.3                                                            3                                    CH.sub.3   (CH.sub.2).sub.4 OH                                                                        C.sub.18 H.sub.37                                                                     C.sub.18 H.sub. 37                                                                     3                                    i-C.sub.3 H.sub.7                                                                        (CH.sub.2).sub.5 OH                                                                        C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                      3                                    C.sub.2 H.sub.5                                                                          CH.sub.2 CH(OCH.sub.3).sub.2                                                               C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                      3                                    CH.sub.2 CHCH.sub.2                                                                       ##STR23##   C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                      3                                    C.sub.6 H.sub.13                                                                          ##STR24##   C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                      3                                    C.sub.6 H.sub.5 O(CH.sub.2).sub.2                                                        CH.sub.2 CH.sub.2 OCH.sub.3                                                                C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                      3                                    ______________________________________                                    

example viiin,n-dioctadecyl-N',N'-Bis[2-(3'-Carboxypropionyloxy)-ethyl]-1,3-Propanediamine

N,N-Dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine (3.335 g.,5 mM.) is added to a solution of succinic anhydride (9.0 g., 90 mM.) ina mixture of ethylacetate (60 ml.) and acetone (60 ml.) at roomtemperature. After stirring for three hours, the reaction mixture iscooled in an ice-bath and the precipitate which forms filtered off,washed with cold acetone and dried. Recrystallization from hotacetone-ethylacetate (1:1) gives the ester as a fine white powder (1.783g.), m.p. 64°-67° C.

The following compounds are prepared from appropriate reactants in likemanner.

    ______________________________________                                         ##STR25##                                                                    R.sub.1  R.sub.2    n       s      R                                          ______________________________________                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3       2     CH.sub.2 CH.sub.2 COOH                      C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3       3     CH.sub.2 CH.sub.2 COOH                      C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3       2     (CH.sub.2).sub.3 COOH                       C.sub.16 H.sub.33                                                                      C.sub.16 H.sub.33                                                                        3       2     CH.sub.2 CH.sub.2 COOH                      C.sub.20 H.sub.41                                                                      C.sub.20 H.sub.41                                                                        3       2     CH.sub.2 CH.sub.2 COOH                      C.sub.14 H.sub.29                                                                      C.sub.14 H.sub.29                                                                        3       2     CH.sub.2 CH.sub.2 COOH                      C.sub.14 H.sub.29                                                                      C.sub.14 H.sub.29                                                                        3       2     (CH.sub.2).sub.3 COOH                       C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3       3     CH.sub.2 CH.sub.2 COOH                      C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3       8     CH.sub.2 CH.sub.2 COOH                      C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3       6     CH.sub.2 CH.sub.2 COOH                      CH.sub.3 C.sub.18 H.sub.37                                                                        3       3     CH.sub.2 CH.sub.2 COOH                      CH.sub.3 C.sub.18 H.sub.37                                                                        3       6     CH.sub.2 CH.sub.2 COOH                      CH.sub.3 C.sub.18 H.sub.37                                                                        3       4     CH.sub.2 CH.sub.2 COOH                      CH.sub.3 C.sub.18 H.sub.37                                                                        3       4     (CH.sub.2).sub.3 COOH                       C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        4       2     CH.sub.2 CH.sub.2 COOH                      C.sub.20 H.sub.41                                                                      C.sub.20 H.sub.41                                                                        2       2     CH.sub.2 CH.sub.2 COOH                      C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        6       2     CH.sub.2 CH.sub.2 COOH                      ______________________________________                                    

example ixn,n-dioctadecyl-N',N'-bis(2-Phenylcarbamoyloxyethyl)-1,3-Propanediamine

Phenyl isocyanate (3.85 g.) is added to a warm solution ofN,NN-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine (5.0 g.)in ethylacetate (20 ml.) and the mixture heated to reflux for one hour.The mixture is cooled, then taken to dryness under reduced pressure. Theresidue is triturated with carbon tetrachloride, filtered, and thefiltrate evaporated to dryness. Ethyl acetate (25 ml.) is then added,the mixture cooled, filtered, washed with ethylacetate and dried invacuo; m.p. 54°-6° C.

The following compounds are prepared from appropriate reactants by thisprocedure:

    ______________________________________                                         ##STR26##                                                                    R.sub.1     R.sub.2      n          s                                         ______________________________________                                        C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          3          3                                         C.sub.16 H.sub.33                                                                         C.sub.16 H.sub.33                                                                          3          2                                         C.sub.20 H.sub.41                                                                         C.sub.20 H.sub.41                                                                          3          2                                         C.sub.14 H.sub.29                                                                         C.sub.14 H.sub.29                                                                          3          2                                         C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          3          3                                         C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          3          8                                         C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          3          6                                         CH.sub.3    C.sub.18 H.sub.37                                                                          3          3                                         CH.sub.3    C.sub.18 H.sub.37                                                                          3          6                                         CH.sub.3    C.sub.18 H.sub.37                                                                          3          4                                         C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          4          2                                         C.sub.18 H.sub.25                                                                         C.sub.12 H.sub.25                                                                          2          2                                         C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          6          2                                         ______________________________________                                    

example xn,n-dioctadecyl-N',N'-bis(2-Palmitoyloxyethyl)-1,3-Propanediamine

Palmitoyl chloride (2.75 g.) is added all at once to a solution ofN,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine (1.334 g.)in ethylacetate (50 ml.) and chloroform (5 ml.) at room temperature. Themixture is stirred for one hour then dry hydrogen chloride gas bubbledin for two minutes. The temperature rose to 42° C. and the initialprecipitate (of the amine salt) which formed dissolved. The mixture ischilled to 5° C. then filtered. The product is washed with ethylacetateand air dried. It is recrystallized from ethylacetate-hexane; m.p.122°-4° C.

Replacement of palmitoyl chloride by acetyl chloride producesN,N-dioctadecyl-N',N'-bis(2-acetyloxyethyl)-1,3-propanediamine. Itshydrochloride salt prepared by standard methods melts at 103°-7° C.

Repetition of this procedure but using the appropriate acid chloride inplace of palmitoyl chloride produces the following compounds:

    ______________________________________                                         ##STR27##                                                                    R.sub.1   R.sub.2    n        s       R                                       ______________________________________                                        C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        3        2      C.sub.5 H.sub.11                         C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        3        2      C.sub.2 H.sub.5                          C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        2        2      C.sub.15 H.sub.31                        C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        2        2      CH.sub.3                                 C.sub.6 H.sub.13                                                                        C.sub.16 H.sub.3                                                                         3        2      C.sub.15 H.sub.31                        C.sub.6 H.sub.13                                                                        C.sub.15 H.sub.3                                                                         3        2      C.sub.3 H.sub.7                          C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        3        3      C.sub.2 H.sub.5                          C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        3        3      C.sub.15 H.sub.31                        C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        4        2      C.sub.17 H.sub.35                        C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        6        2      C.sub.15 H.sub.31                        C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        3        8      CH.sub.3                                 C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                        3        8      C.sub.17 H.sub.35                        ______________________________________                                    

example xi 1,1-dioctadecyl-3-{2-[Bis(2-Hydroxyethyl)Amino]Ethyl}Urea

A mixture of N,N-dioctadecylcarbamyl chloride (2.9 g.),N,N-bis(2-hydroxyethyl)-1,2-ethanediamine (4.0 g.) and benzene (50 ml.)is refluxed and stirred for three hours. The mixture is then cooled,concentrated in vacuo and the residue taken up on chloroform (100 ml.).The chloroform solution is washed successively with water (2× 50 ml.),aqueous sodium hydroxide (1× 50 ml. of 1 N) and water (2× 50 ml.), thendried (Na₂ SO₄). Removal of the chloroform in vacuo leaves the crudeproduct as an oil (3.3 g.).

It is purified by chromatography on silica gel and elution withethylacetate.

The hydrochloride salt is obtained by dissolving the purified product(0.75 g.) in ether (30 ml.) and bubbling in dry hydrogen chloride gas.Concentration of the ether provides the salt; 0.55 g., m.p. 152°-153° C.

The N,N-dioctadecylcarbamyl chloride is prepared by bubbling phosgeneinto a solution of N,N-dioctadecylamine (100 g.) in chloroform (1.2liters) at room temperature for three hours. The mixture is stirred fortwo hours, then filtered. The filtrate is evaporated to provide theproduct (48 g.).

The following urea derivatives are similarly prepared but substitutingN,N-bis(2-hydroxyethyl)-1,2-ethanediamine by the appropriate reactant:

    ______________________________________                                         ##STR28##                                                                     ##STR29##                                                                    R.sub.3   R.sub.4     m      n   Salt M.P. (° C.)                      ______________________________________                                        CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH                                                                       1      3   --   53-5                                    CH.sub.3 CH.sub.3     1      2   HCl  71-4                                    CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH                                                                       1      5   HCl  120-3                                   H        CH.sub.2 CH.sub.2 OH                                                                       0      --  --   60-1                                    CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH                                                                       0      --  --   46-7                                    H        CH.sub.2 CH.sub.2 OCH.sub.3                                                                0      --  --   44-5                                    CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH                                                                       1      2   HCl  152-3                                   H        CH.sub.2 CH.sub.2 COOH                                                                     0      --  --   77-81                                   H        H            0      --  --   61-2                                    CH.sub.2CH.sub.2OCH.sub.2CH.sub.2                                                               0      --    --   42-4                                      ______________________________________                                    

the compounds listed below are prepared in like manner from theappropriate reactants.

    __________________________________________________________________________    The compounds listed below are prepared in like manner from                   the appropriate reactants.                                                     ##STR30##                                                                    R.sub.1                                                                             R.sub.2                                                                           R.sub.3       R.sub.4       m n                                     __________________________________________________________________________    C.sub.6 H.sub.5 OCH.sub.2                                                           C.sub.18 H.sub.37                                                                 C.sub.2 H.sub.5                                                                             C.sub.18 H.sub.37                                                                           1 3                                     C.sub.6 H.sub.5 OCH.sub.2                                                           C.sub.12 H.sub.25                                                                 C.sub.16 H.sub.33                                                                           C.sub.16 H.sub.33                                                                           1 3                                     C.sub.6 H.sub.5 OCH.sub.2                                                           C.sub.12 H.sub.25                                                                 C.sub.16 H.sub.33                                                                           C.sub.16 H.sub.33                                                                           1 5                                     C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 (CH.sub.2).sub.8 OH                                                                         (CH.sub.2).sub.8 OH                                                                         0 --                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 (CH.sub.2).sub.8 OH                                                                         (CH.sub.2).sub.8 OH                                                                         1 3                                     C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 (CH.sub.2).sub.8 OH                                                                         (CH.sub.2).sub.8 OH                                                                         1 6                                     C.sub.14 H.sub. 29                                                                  C.sub.14 H.sub.29                                                                 H             CH.sub.2 CH.sub.2 CH.sub.2 OH                                                               0 --                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 COOCH.sub.3                                                                        CH.sub.2 COOCH.sub.3                                                                        1 3                                     C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 COOCH.sub.3                                                                        CH.sub.2 COOCH.sub.3                                                                        0 --                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2CHCH.sub.2                                                                          CH.sub.2CHCH.sub.3                                                                          0 --                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2CHCH.sub.2                                                                          CH.sub.2CHCH.sub.2                                                                          1 3                                     C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCOCH.sub.3                                                               CH.sub.2 CH.sub.2 OCOCH.sub.3                                                               1 3*                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCOCH.sub.3                                                               CH.sub.2 CH.sub.2 OCOCH.sub.3                                                               1 5*                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCOC.sub.15 H.sub.31                                                      CH.sub.2 CH.sub.2 OCOC.sub.15 H.sub.31                                                      1 3*                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCOC.sub.15 H.sub.31                                                      CH.sub.2 CH.sub.2 OCOC.sub.15 H.sub.31                                                      1 5*                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2  H.sub.2 OCOC.sub.15 H.sub.31                                                      CH.sub.2 CH.sub.2 OCOC.sub.15 H.sub.31                                                      0 --*                                   C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5                                                      CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5                                                      0 --*                                   C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5                                                      CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5                                                      1 2*                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5                                                      CH.sub.2 CH.sub.2 OCONHC.sub.6 H.sub.5                                                      1 5*                                    C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCOCH.sub.2 CH.sub.2 COOH                                                 CH.sub.2 CH.sub.2 OCOCH.sub.2 CH.sub.2 COOH                                                 0 --*                                   C.sub.18 H.sub.37                                                                   C.sub.18 H.sub.37                                                                 CH.sub.2 CH.sub.2 OCOCH.sub.2 CH.sub.2 COOH                                                 CH.sub.2 CH.sub.2 OCOCH.sub.2 CH.sub.2 COOH                                                 1 3*                                    __________________________________________________________________________     *Prepared from the corresponding hydroxyalkyl compounds of this example b     the reactions of Examples VIII - X.                                      

EXAMPLE XII N-(2-Hydroxyethyl)Octadecylamine

A mixture of octadecyl bromide (6.66 g., 0.02 mole), ethanolamine (0.61g., 0.01 mole), potassium carbonate (4.14 g., 0.03 mole) and benzylalcohol (4 ml.) is heated overnight at 135°-145° C. The mixture iscooled, treated with ethylacetate (50 ml.) and 10 percent aqueous sodiumhydroxide (10 ml.). The ethylacetate layer is separated, washed withwater, and dried (Na₂ SO₄). Removal of the organic solvents underreduced pressure gives an oily residue which solidifies upon cooling. Itis purified by chromatography on alumina with chloroform as eluant. Itshydrobromide salt is prepared by adding hydrogen bromide to an ethanolsolution of the base. It melts at 172°-173° C.

The compounds tabulated below are prepared from the appropriatereactants A--Y--Br and H--NR₅ R₆ by the above procedure:

    ______________________________________                                         ##STR31##                                                                    Y       A           R.sub.5 R.sub.6                                                                             Salt M.P. (° C.)                     ______________________________________                                        (CH.sub.2).sub.3                                                                      OH          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   HBr  78-82                                  (CH.sub.2).sub.3                                                                      OH          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   37-40                                  (CH.sub.2).sub.3                                                                      OH          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   38-42                                  (CH.sub.2).sub.6                                                                      OH          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   (a wax)                                (CH.sub.2).sub.2                                                                      CN.sup.(a)  C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   57-58                                  (CH.sub.2).sub.2                                                                      CN          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   HCl  73-74                                  (CH.sub.2).sub.2                                                                      OH          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   35-37                                  (CH.sub.2).sub.2                                                                      OH          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   HBr  74-78                                  (CH.sub.2).sub.2                                                                      OCOCH.sub.3.sup.(b)                                                                       C.sub. 18 H.sub.37                                                                    C.sub.18 H.sub.37                                                                   --   32-35                                  (CH.sub.2).sub.2                                                                      OC.sub.2 H.sub.5                                                                          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   <30                                    (CH.sub.2).sub.3                                                                      OCONHC.sub.6 H.sub.5.sup.(b)                                                              C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   197-198                                (CH.sub.2).sub.3                                                                      Br          C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   116-119                                (CH.sub.2).sub.3                                                                      CHO         C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   52-52.5                                (CH.sub.2).sub.3                                                                      OCOCH.sub.3.sup.(b)                                                                       C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --   (a wax)                                (CH.sub.2).sub.2                                                                      CN.sup.(a)  C.sub.18 H.sub.37                                                                     H     --   84-85                                  ______________________________________                                         .sup.(a) Prepared by cyanoethylation procedure of Vogel et al., J.C.S.        514-49 (1952).                                                                .sup.(b) The acyl and carbamyl derivatives are prepared by the standard       methods described by Shriner et al., "The Systematic Identification of        Organic Compounds," John Wiley & Sons, Inc., New York, 1956, pp. 212 and      211, respectively.                                                       

EXAMPLE XIII

The procedure of Example XI is followed using the appropriate reactantsA--Y--NHR₆ and R₅ --Br to give the compounds listed below:

    ______________________________________                                         ##STR32##                                                                    Y           A              R.sub.5   R.sub.6                                  ______________________________________                                        (CH.sub.2).sub.3                                                                         CN              CH.sub.3  C.sub.18 H.sub.37                        (CH.sub.2).sub.3                                                                         CN              C.sub.6 H.sub.13                                                                        C.sub.16 H.sub.33                        (CH.sub.2).sub.2                                                                         OH              C.sub.2 H.sub.5                                                                         C.sub.12 H.sub.25                        (CH.sub.2).sub.6                                                                         OH              C.sub.2 H.sub.5                                                                         C.sub.12 H.sub.25                        (CH.sub.2).sub.6                                                                         Br              C.sub.12 H.sub.25                                                                       C.sub.12 H.sub.25                        (CH.sub.2).sub.5                                                                         Br              C.sub.14 H.sub.29                                                                       C.sub.14 H.sub.29                        (CH.sub.2).sub.5                                                                         OCOCH.sub.3     C.sub.12 H.sub.25                                                                       C.sub.12 H.sub.25                        (CH.sub.2).sub.5                                                                         OCOC.sub.3 H.sub.7                                                                            C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.3                                                                         OCH.sub.3       C.sub.16 H.sub.33                                                                       C.sub.16 H.sub.33                        (CH.sub.2).sub.3                                                                         OCH.sub.3       C.sub.12 H.sub.25                                                                       C.sub.12 H.sub.25                        (CH.sub.2).sub.4                                                                         OC.sub.4 H.sub.9                                                                              C.sub.10 H.sub.21                                                                       C.sub.10 H.sub. 21                       (CH.sub.2).sub.5                                                                         OCONHC.sub.6 H.sub.5                                                                          H         C.sub.16 H.sub.33                        (CH.sub.2).sub.2                                                                         OCOCH.sub.2 CH.sub.2 COOH                                                                     C.sub.14 H.sub.29                                                                       C.sub.14 H.sub.29                        (CH.sub.2).sub.2                                                                         OCOCH.sub.2 CH.sub.2 COOH                                                                     C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.6                                                                         OCOCH.sub.2 CH.sub.2 COOH                                                                     C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.3                                                                         OCOC.sub.2 H.sub.5                                                                            C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.4                                                                         OCOC.sub.2 H.sub.5                                                                            C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.2                                                                         OCOC.sub.2 H.sub.5                                                                            C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.3                                                                         OCOC.sub.15 H.sub.31                                                                          C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.3                                                                         OCOC.sub.15 H.sub.31                                                                          C.sub.12 H.sub.25                                                                       C.sub.12 H.sub.25                        (CH.sub.2).sub.2                                                                         COOCH.sub.3     C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.3                                                                         COOC.sub.15 H.sub.31                                                                          C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.3                                                                         COOC.sub. 15 H.sub.31                                                                         C.sub.16 H.sub.33                                                                       C.sub.16 H.sub.33                        (CH.sub.2).sub.5                                                                         Cl              C.sub.2 H.sub.5                                                                         C.sub.12 H.sub.25                        (CH.sub.2).sub.5                                                                         CN              C.sub.2 H.sub.5                                                                         C.sub.12 H.sub.25                        (CH.sub.2).sub.5                                                                         COOC.sub.2 H.sub.5                                                                            C.sub.12 H.sub.25                                                                       C.sub.12 H.sub.25                        (CH.sub.2).sub.4                                                                         COOC.sub.2 H.sub.5                                                                            C.sub.16 H.sub.33                                                                       C.sub.16 H.sub.33                        (CH.sub.2).sub.4                                                                         COOC.sub.9 H.sub.19                                                                           C.sub.16 H.sub.33                                                                       C.sub.16 H.sub.33                        (CH.sub.2).sub.8                                                                         OH              C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.8                                                                         Cl              C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.8                                                                         CN              C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        (CH.sub.2).sub.8                                                                         OC.sub.2 H.sub.5                                                                              C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                        ______________________________________                                    

    ______________________________________                                        r.sub.5r.sub.6                                                                 ##STR33##                                                                    a        y         r° r'      r"                                       ______________________________________                                        ho       (ch.sub.2).sub.2                                                                        4-oc.sub.18 h.sub.37                                                                    h       h                                        ho       (ch.sub.2).sub.3                                                                        4-oc.sub.18 h.sub.37                                                                    h       h                                        ho       (ch.sub.2).sub.3                                                                        3-oc.sub.6 h.sub.13                                                                     4-oc.sub.6 h.sub.13                                                                   h                                        ho       (ch.sub.2).sub.6                                                                        3-oc.sub.6 h.sub.13                                                                     4-oc.sub.6 h.sub.13                                                                   h                                        ho       (ch.sub.2).sub.3                                                                        2-och.sub.3                                                                             4-oc.sub.12 h.sub.25                                                                  5-och.sub.3                              ho       (ch.sub.2).sub.4                                                                        2-oc.sub.6 h.sub.13                                                                     3-oc.sub.2 h.sub.5                                                                    h                                        ho       (ch.sub.2).sub.3                                                                        3-oc.sub.12 h.sub.25                                                                    4-oc.sub.2 h.sub.5                                                                    h                                        ho       (ch.sub.2).sub.2                                                                        4-oc.sub.18 h.sub.37                                                                    2-ch.sub.3                                                                            6-ch.sub.3                               ho       (ch.sub.2).sub.8                                                                        4-oc.sub.8 h.sub.17                                                                     h       h                                        cn       (ch.sub.2).sub.2                                                                        4-oc.sub.18 h.sub. 37                                                                   h       h                                        cn       (ch.sub.2).sub.2                                                                        2-och.sub.3                                                                             4-oc.sub.12 h.sub.25                                                                  5-och.sub.3                              cn       (ch.sub.2).sub.2                                                                        2-oc.sub.6 h.sub.13                                                                     3-oc.sub.2 h.sub.5                                                                    h                                        cn       (ch.sub.2).sub.5                                                                        4-oc.sub.8 h.sub.17                                                                     h       h                                        cl       (CH.sub.2).sub.3                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        Cl       (CH.sub.2).sub.6                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        Cl       (CH.sub.2).sub.3                                                                        4-OC.sub.14 H.sub.29                                                                    H       H                                        Br       (CH.sub.2).sub.3                                                                        4-OC.sub.14 H.sub.29                                                                    H       H                                        Br       (CH.sub.2).sub.3                                                                        2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                  5-OCH.sub.3                              Cl       (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    2-CH.sub.3                                                                            6-CH.sub.3                               OCOCH.sub.3                                                                            (CH.sub.2).sub.2                                                                        4-OC.sub.18 H.sub.37                                                                    H       H                                        OCOC.sub.3 H.sub.7                                                                     (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    H       H                                        OCOC.sub.15 H.sub.31                                                                   (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    2-CH.sub.3                                                                            6-CH.sub.3                               OCO.sub.10 H.sub.21                                                                    (CH.sub.2).sub.3                                                                        2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                  5-OCH.sub.3                              OCOC.sub.3 H.sub.7                                                                     (CH.sub.2).sub.4                                                                        2-OC.sub.6 H.sub.13                                                                     3-OC.sub.2 H.sub.5                                                                    H                                        OCOC.sub.4 H.sub.9                                                                     (CH.sub.2).sub.3                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        OCOC.sub.4 H.sub.9                                                                     (CH.sub.2).sub.6                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        OCOC.sub.17 H.sub.35                                                                   (CH.sub.2).sub.8                                                                        4-OC.sub.8 H.sub.17                                                                     H       H                                        COOC.sub.2 H.sub.5                                                                     (CH.sub.2).sub.2                                                                        4-OC.sub.18 H.sub.37                                                                    H       H                                        COOCH.sub.3                                                                            (CH.sub.2).sub.3                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        COOCH.sub.3                                                                            (CH.sub.2).sub.6                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        COOC.sub.2 H.sub.5                                                                     (CH.sub.2).sub.4                                                                        2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                  5-OCH.sub.3                              COOC.sub.2 H.sub.5                                                                     (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    2-CH.sub.3                                                                            6-CH.sub.3                               OCH.sub.3                                                                              (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    2-CH.sub.3                                                                            6-CH.sub.3                               OCH.sub.3                                                                              (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    H       H                                        OCH.sub.3                                                                              (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    H       H                                        OC.sub.6 H.sub.13                                                                      (CH.sub.2).sub.3                                                                        4-OC.sub.18 H.sub.37                                                                    H       H                                        OCH.sub.3                                                                              (CH.sub.2).sub.3                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        OC.sub.10 H.sub.21                                                                     (CH.sub.2).sub.3                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        OC.sub.17 H.sub.35                                                                     (CH.sub.2).sub.3                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        O-n-C.sub.4 H.sub.9                                                                    (CH.sub.2).sub.3                                                                        2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                  5-OCH.sub.3                              OCONHC.sub.6 H.sub.5                                                                   (CH.sub.2).sub.2                                                                        4-OC.sub.18 H.sub.37                                                                    H       H                                        OCONHC.sub.6 H.sub.5                                                                   (CH.sub.2).sub.3                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        OCONHC.sub.6 H.sub.5                                                                   (CH.sub.2).sub.6                                                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                   H                                        OCONHC.sub.6 H.sub.5                                                                   (CH.sub.2).sub.4                                                                        2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                  5-OCH.sub.3                              ______________________________________                                    

example xiv n,n-dioctadecylsuccinamate

Dioctadecylamine (5.21 g., 0.01 mole) and succinic anhydride (0.50 g.,0.005 mole) are heated overnight at 105° C. on an oil bath. The mixtureis poured over ice and the solid which forms separated by filtration;4.9 g.; m.p. 57°-62° C. It is dissolved in chloroform (50 ml.) and thesolution extracted with 6 N hydrochloric acid (3× 50 ml.). (The solidwhich formed at the interface is removed by filtration).

The chloroform phase is separated, washed with saturated aqueous sodiumcarbonate (3× 50 ml.) and the emulsion which forms allowed to separateovernight. The chloroform layer is separated, dried (Na₂ SO₄) andconcentrated in vacuo to an oil. Trituration of the oil with acetoneproduces a brown solid; 2.03 g.; m.p. 52°-58° C. Recrystallization fromethyl acetate raises the melting point to 77°-81° C.

The following compounds are made from appropriate reactants (anhydridesand amines) by this procedure:

    ______________________________________                                         ##STR34##                                                                    Y'       R.sub.5      R.sub.6                                                 ______________________________________                                        CH.sub.2 CH.sub.2                                                                      C.sub.16 H.sub.33                                                                          C.sub.16 H.sub.33                                       CH.sub.2 CH.sub.2                                                                      C.sub.16 H.sub.33                                                                          C.sub.16 H.sub.33                                       CH.sub.2 CH.sub.2                                                                      CH.sub.3     C.sub.18 H.sub.37                                       (CH.sub.2).sub.3                                                                       C.sub.18 H.sub.37                                                                          C.sub.18 H.sub.37                                       (CH.sub.2).sub.3                                                                       C.sub.12 H.sub.25                                                                          C.sub.12 H.sub.25                                       (CH.sub.2).sub.3                                                                       C.sub.18 H.sub.37                                                                          H                                                       (CH.sub.2).sub.3                                                                       C.sub.12 H.sub.25                                                                          C.sub.12 H.sub.25                                       CH.sub.2 CH.sub.2                                                                      H            C.sub.12 H.sub.25                                       CH.sub.2 CH.sub.2                                                                      H            C.sub.16 H.sub.33                                       (CH.sub.2).sub.3                                                                       H            C.sub.20 H.sub.41                                        ##STR35##                                                                    Y'       R°    R'          R"                                          ______________________________________                                        CH.sub.2 CH.sub.2                                                                      4-OC.sub.18 H.sub.37                                                                       H           H                                           (CH.sub.2 ).sub.3                                                                      4-OC.sub.18 H.sub.37                                                                       H           H                                           (CH.sub.2).sub.3                                                                       3-OC.sub.6 H.sub.13                                                                        4-OC.sub.6 H.sub.13                                                                       H                                           CH.sub.2 CH.sub.2                                                                      3-OC.sub.6 H.sub.13                                                                        4-OC.sub.6 H.sub.13                                                                       H                                           CH.sub.2 CH.sub.2                                                                      3,4-OCH.sub.2O       H                                               CH.sub.2 CH.sub.2                                                                      4,5-OCH.sub.2O       2-C.sub.3 H.sub.7                               CH.sub.2 CH.sub.2                                                                      2-OCH.sub.3  4-OC.sub.12 H.sub.25                                                                      5-OCH.sub.3                                 (CH.sub.2).sub.3                                                                       3,4-OCH.sub.2O       H                                               (CH.sub.2).sub.3                                                                       4-OC.sub.8 H.sub.17                                                                        H           H                                           (CH.sub.2).sub.3                                                                       4-OC.sub.18 H.sub.37                                                                       2-CH.sub.3  6-CH.sub.3                                  CH.sub.2 CH.sub.2                                                                      4-OC.sub.18 H.sub.37                                                                       2-CH.sub.3  6-CH.sub.3                                  ______________________________________                                    

example xv n-(3-dodecyloxypropyl)Diethanolamine andN-(3-Dodecyloxypropyl)Monoethanolamine

A mixture of bromoethanol (2.50 g., 0.05 mole),3-dodecyloxy-1-propylamine (2.43 g., 0.01 mole) and ethanol (20 ml.) isheated at reflux overnight. The solvent is removed by evaporation, theresidue slurried in hot water (20 ml.) and made strongly alkaline withpotassium hydroxide. The basic mixture is extracted with ether (3× 50ml.), the ethereal extracts dried (MgSO₄) and evaporated. The crudeproduct mixture is purified by chromatography on alumina. Using ether aseluant removes the least polar impurity; elution with methanol removesthe diethanolamine first, then the monoethanolamine derivative.

These two products appear as blue and yellow spots, respectively, whensubjected to thin layer chromatography on a silica plate with methanolas eluant and iodoplatinic spray as developer.

The monoethanolamine derivatives boils at 160°-166° C. at 0.3 mm.mercury.

The following compounds are prepared in like manner from appropriatereactants: A'--O--(CH₂)_(n) --NH₂ and Br--R₅

    ______________________________________                                         ##STR36##                                                                    A'    n      R.sub.5    R.sub.6                                                                             Salt    M.P. (° C.)                      ______________________________________                                        C.sub.12 H.sub.25                                                                   2     CH.sub.3    CH.sub.3                                                                            CH.sub.3 I                                                                            165-7                                   C.sub.18 H.sub.37                                                                   3     CH.sub.3    H     HI      210-I                                   C.sub.18 H.sub.37                                                                   3     CH.sub.2 CH.sub.2 OH                                                                      H     HBr                                             ______________________________________                                    

EXAMPLE XVI N-(3-Dodecylthiopropyl)Diethanolamine

A mixture of 3-octadecylthiopropyl chloride (3.53 g., 0.01 mole),diethanolamine (2.1 g., 0.02 mole) and benzyl alcohol (5 ml.) is heatedunder reflux for one-half hour, then treated with an ethanolic solutionof sodium hydroxide (0.4 g., 0.01 mole) and refluxed for five moreminutes. The mixture is cooled, filtered, and the ethanol removed byevaporation. The benzyl alcohol is then removed by distillation in vacuoand the residue chromatographed on silica using first ether thenmethanol as eluants. The desired product is contained in the methanoleluate. It is isolated by evaporation of the solvent, m.p. 53°-54° C.Its hydrochloride salt melts at 65°-66° C.

In like manner, the following compounds are prepared from theappropriate reactants: A'--S--(CH₂)_(n) --Cl and H--NR₅ R₆

    ______________________________________                                         ##STR37##                                                                    A'    n      R.sub.5     R.sub.6                                                                              Salt  M.P. (° C.)                      ______________________________________                                        C.sub.18 H.sub.37                                                                   3     CH.sub.2 CH.sub.2 OH                                                                      H       --                                            C.sub.18 H.sub.37                                                                   3     CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        H       --    155-7                                   C.sub.16 H.sub.33                                                                   3     CH.sub.2 CH.sub.2 OH                                                                      H       --                                            C.sub.16 H.sub.33                                                                   3     CH.sub.2 CH.sub.2 OH                                                                      CH.sub.2 CH.sub.2 OH                                                                  HCl   129-130                                 C.sub.14 H.sub.29                                                                   3     CH.sub.2 CH.sub.2 OH                                                                      CH.sub.2 CH.sub.2 OH                                                                  --    30-1                                    C.sub.14 H.sub.29                                                                   3     CH.sub.2 CH.sub.2 OH                                                                      CH.sub.2 CH.sub.2 OH                                                                  HCl   72 (dec.)                               C.sub.16 H.sub.33                                                                   2     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                       --    175-8                                                                          (0.3 mm.)                              C.sub.18 H.sub.37                                                                   2     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                       --    170-4                                                                          (0.2 mm.)                              C.sub.18 H.sub.37                                                                   2     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                       HCl   102-4                                   C.sub.18 H.sub.37                                                                   2     (CH.sub.2).sub.3 N(C.sub.2 H.sub.5).sub.2                                                 H       2HCl                                          ______________________________________                                    

EXAMPLE XVII

Following the procedures of Examples XV and XVI the compounds listedbelow are prepared from appropriate reactants:

    __________________________________________________________________________     ##STR38##                                                                     A    n  R.sub.5                                                                            R.sub.6                                                                            A    n  R.sub.5                                                                            R.sub.6                                       __________________________________________________________________________    CH.sub.3 O                                                                          2 C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  C.sub.12 H.sub.25 O                                                                 3 C.sub.18 H.sub.37                                                                  H                                              C.sub.12 H.sub.25 O                                                                 3 C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  C.sub.6 H.sub.5 S                                                                   3 C.sub.10 H.sub.21                                                                  C.sub.10 H.sub.21                              C.sub.2 H.sub.5 O                                                                   6 C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37 S                                                                 3 C.sub.18 H.sub.37                                                                  H                                              C.sub.18 H.sub.37 O                                                                 3 C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37 S                                                                 3 C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                              C.sub.6 H.sub.13 O                                                                  3 C.sub.16 H.sub.33                                                                  C.sub.16 H.sub.33                                                                  C.sub.16 H.sub.33 S                                                                 2 C.sub.12 H.sub.25                                                                  C.sub.12 H.sub.25                                                C.sub.16 H.sub.33 S                                                                 2 H    C.sub.12 H.sub.25                                                CH.sub.3 S                                                                          6 C.sub.18 H.sub. 37                                                                 C.sub.18 H.sub.37                               ##STR39##                                                                     A    n  R°                                                                            R'     R"                                                     __________________________________________________________________________    C.sub.18 H.sub.37 O                                                                 3 4-OC.sub.18 H.sub.37                                                                 H      H                                                       C.sub.18 H.sub.37 O                                                                 3 3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H                                                       C.sub.18 H.sub.37 O                                                                 3 2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                             C.sub.18 H.sub.37 O                                                                 3 4,5-OCH.sub.2O                                                                              2-C.sub.3 H.sub.7                                       C.sub.18 H.sub.37 O                                                                 3 4-OC.sub.8 H.sub.17                                                                  H      H                                                       C.sub.18 H.sub.37 O                                                                 2 3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H                                                       C.sub.16 H.sub.33 O                                                                 2 3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H                                                       C.sub.16 H.sub.33 O                                                                 3 3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H                                                       C.sub.16 H.sub.33 O                                                                 3 4-OC.sub.18 H.sub.37                                                                 2-CH.sub.3                                                                           6-CH.sub.3                                              CH.sub. 3 O                                                                         3 4-OC.sub.18 H.sub.37                                                                 2-CH.sub.3                                                                           6-CH.sub.3                                              C.sub.6 H.sub.13 O                                                                  3 4-OC.sub.18 H.sub.37                                                                 2-CH.sub.3                                                                           6-CH.sub.3                                              C.sub.2 H.sub.5 O                                                                   3 3,4-OCH.sub.2O                                                                              H                                                       CH.sub.3 O                                                                          2 3,4-OCH.sub.2O                                                                              H                                                       C.sub.10 H.sub.21 O                                                                 3 2-OC.sub.6 H.sub.13                                                                  3-OC.sub.2 H.sub.5                                                                   H                                                       CH.sub.3 O                                                                          6 3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H                                                       C.sub.10 H.sub.21 O                                                                 5 4-OC.sub.18 H.sub.37                                                                 H      H                                                       CH.sub.3 O                                                                          6 4-OC.sub.14 H.sub.29                                                                 H      H                                                       C.sub.4 H.sub.9 S                                                                   2 4-OC.sub.14 H.sub.29                                                                 H      H                                                       C.sub.12 H.sub.25 S                                                                 4 4-OC.sub.18 H.sub.37                                                                 H      H                                                       C.sub.12 H.sub.25 S                                                                 4 3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H                                                       C.sub.10 H.sub.21 S                                                                 5 3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H                                                       CH.sub.3 S                                                                          6 4-OC.sub.18 H.sub.37                                                                 H      H                                                       C.sub.18 H.sub.37 S                                                                 3 4-OC.sub.18 H.sub.37                                                                 H      H                                                       C.sub.18 H.sub.33 S                                                                 2 3,4-OCH.sub.2O                                                                              H                                                       C.sub.10 H.sub.21 S                                                                 4 4-OC.sub.8 H.sub.17                                                                  H      H                                                       __________________________________________________________________________

example xviii n-(2-dodecanoylthioethyl)Diethylamine

Decanoyl chloride (1.90 g., 0.01 mole) in ether (250 ml.) is added to amixture of diethylaminoethanoethiol (1.33 g., 0.01 mole) andtriethylamine (1.01 g., 0.01 mole) in ether (250 ml.) and the reactionmixture stirred overnight at room temperature. The white precipitate isfiltered off and the filtrate evaporated in vacuo to provide theproduct.

In like manner, N-(2-dodecanoyloxyethyl)diethylamine is prepared fromdecanoyl chloride and diethylaminoethanol. It boils at 103°-106° C. at0.05 mm. mercury.

The following compounds are likewise prepared from appropriate reactantsby this procedure:

    ______________________________________                                         ##STR40##                                                                    A"      R.sub.5   R.sub.6   t                                                 ______________________________________                                        C.sub.17 H.sub.35 CO                                                                  n-C.sub.4 H.sub.9                                                                       CH.sub.2 CH.sub.2 OH                                                                    3                                                 C.sub.9 H.sub.19 CO                                                                   C.sub.16 H.sub.33                                                                       C.sub.16 H.sub.33                                                                       5                                                 C.sub.13 H.sub.27 CO                                                                  CH.sub.2 CH.sub.2 OH                                                                    CH.sub.2 CH.sub.2 OH                                                                    2                                                 C.sub.11 H.sub.23 CO                                                                  C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                       2                                                 C.sub.2 H.sub.5 CO                                                                    C.sub.20 H.sub.41                                                                       C.sub.20 H.sub.41                                                                       2                                                 C.sub.11 H.sub.23 CO                                                                  C.sub.20 H.sub.41                                                                       C.sub.20 H.sub.41                                                                       2                                                 C.sub.11 H.sub.23 CO                                                                  (CH.sub.2).sub.4 OH                                                                     (CH.sub.2).sub.4 OH                                                                     3                                                 C.sub.11 H.sub.23 CO                                                                  C.sub.18 H.sub.37                                                                       C.sub.18 H.sub.37                                                                       6                                                  ##STR41##                                                                     A"       R°   R'          R"     t                                    ______________________________________                                        CH.sub.3 CO                                                                            4-OC.sub.18 H.sub.37                                                                      2-CH.sub.3  6-CH.sub.3                                                                            2                                    CH.sub.3 CO                                                                            3-OC.sub.6 H.sub.13                                                                       4-OC.sub.6 H.sub.13                                                                       H       3                                    CH.sub.3 CO                                                                            2-OCH.sub.3 4-OC.sub.12 H.sub.25                                                                      5-OCH.sub.3                                                                           3                                    CH.sub.3 CO                                                                            4,5-OCH.sub.2O      2-C.sub.3 H.sub.7                                                                       6                                      C.sub.3 H.sub.7 CO                                                                     4-OC.sub.18 H.sub.37                                                                      2-CH.sub.3  6-CH.sub.3                                                                            2                                    C.sub.3 H.sub.7 CO                                                                     4-OC.sub.14 H.sub.29                                                                      H           H       3                                    C.sub.3 H.sub.7 CO                                                                     3-OC.sub.6 H.sub.13                                                                       4-OC.sub.6 H.sub.13                                                                       H       6                                    C.sub.17 H.sub.35 CO                                                                   3-OC.sub.6 H.sub.13                                                                       4-OC.sub.6 H.sub.13                                                                       H       6                                    C.sub.17 H.sub.35 CO                                                                   3-OC.sub.6 H.sub.13                                                                       4-OC.sub.6 H.sub.13                                                                       H       3                                    C.sub.17 H.sub.35 CO                                                                   4-OC.sub.14 H.sub.29                                                                      H           H       3                                    C.sub.17 H.sub.35 CO                                                                   4,5-OCH.sub.2O      2-C.sub.3 H.sub.7                                                                       3                                      C.sub.12 H.sub.25 CO                                                                   4-OC.sub.18 H.sub.37                                                                      H           H       3                                    C.sub.7 H.sub.15 CO                                                                    4-OC.sub.18 H.sub.37                                                                      H           H       3                                    CH.sub.3 CO                                                                            4-OC.sub.18 H.sub.37                                                                      H           H       3                                    C.sub.12 H.sub.25 CO                                                                   4-OC.sub.18 H.sub.37                                                                      H           H       6                                    C.sub.2 H.sub.5 CO                                                                     4-OC.sub.18 H.sub.37                                                                      H           H       6                                    C.sub.5 H.sub.11 CO                                                                    3-OC.sub.6 H.sub.13                                                                       4-OC.sub.6 H.sub.13                                                                       H       6                                    C.sub.11 H.sub.23 CO                                                                   3-OC.sub.6 H.sub.13                                                                       4-OC.sub.6 H.sub.13                                                                       H       6                                    CH.sub.3 CO                                                                            3,4-OCH.sub.2O      H         6                                      C.sub.9 H.sub.19 CO                                                                    3,4-OCH.sub.2O      H         6                                      C.sub.7 H.sub.15 CO                                                                    4-OC.sub.18 H.sub.37                                                                      2-CH.sub.3  6-CH.sub.3                                                                            6                                    C.sub.13 H.sub.27 CO                                                                   4-OC.sub.18 H.sub.37                                                                      2-CH.sub.3  6-CH.sub.3                                                                            3                                    ______________________________________                                    

example xix ethyl 4-Dioctadecylaminobutyrate

A solution of dioctadecylamine (5.2 g., 0.01 mole), ethyl4-bromobutyrate (1.95 g., 0.01 mole) and toluene (50 ml.) is heated atreflux for sixteen hours, then cooled and concentrated in vacuo to asemi-solid oil. The oil is triturated with ethylacetate, filtered, andthe filtrate washed with water, then dried (Na₂ SO₄). Removal of thesolvent gives the product as an oil (3.7 g.).

It is purified by chromatography on silica gel and elution of the columnfirst with benzene, then with benzene containing 20 percentethylacetate.

The residue obtained by evaporation of the benzene-20 percentethylacetate solvent is taken up in ethylacetate and converted to thehydrochloride salt by bubbling dry hydrogen chloride through thesolution. Concentration of the mixture in vacuo provides a crystallinematerial; m.p. 98°-101° C.

Substitution of ethyl 4-bromobutyrate by the appropriate lower alkylω-bromoalkanoate in the above procedure produces the followingcompounds:

    ______________________________________                                         ##STR42##                                                                     A       Y         R.sub.5                                                                               R.sub.6                                                                            Salt  M.P. (° C.)                      ______________________________________                                        COOC.sub.2 H.sub.5                                                                    CH.sub.2  C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   --    40                                      COOC.sub.2 H.sub.5                                                                    (CH.sub.2).sub.4                                                                        C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   HCl   46-48                                   COOC.sub.2 H.sub.5                                                                    (CH.sub.2).sub.2                                                                        C.sub.18 H.sub.37                                                                     C.sub.18 H.sub.37                                                                   HCl   52-53                                   ______________________________________                                    

EXAMPLE XX 1-(N,N-Dioctadecylcarbamyl)-4-Methylpiperazine

A mixture of 1-methylpiperazine (5 ml.), N,N-dioctadecylcarbamylchloride(5.0 g.) and benzene (50 ml.) is refluxed and stirred for three hours.The white precipitate of 1-methylpiperazine hydrochloride is removed byfiltration and the filtrate concentrated in vacuo to a yellow oil (4.5g.). The oil is then charged on a silica gel pad and eluted with benzenein 50 ml. fractions. Fractions 10-15 are combined, a large volume ofmethanol added and the white crystalline material which separatesfiltered and dried, m.p. 46°-47° C. (1.45 g.).

The following compounds are prepared from the appropriate reactants (R₇R₈ NCOCl and H-Z):

    ______________________________________                                         ##STR43##                                                                     R.sub.7                                                                              R.sub.8    Z                                                          ______________________________________                                        C.sub.12 H.sub.25                                                                    C.sub.12 H.sub.25                                                                      butylpiperazino                                               C.sub.12 H.sub.25                                                                    C.sub.12 H.sub.25                                                                      piperidino                                                    C.sub.12 H.sub.25                                                                    C.sub.12 H.sub.25                                                                      morpholino                                                    C.sub.18 H.sub.37                                                                    CH.sub.3 methylpiperazino                                              C.sub.18 H.sub.37                                                                    CH.sub.3 morpholino                                                    C.sub.18 H.sub.37                                                                    C.sub.18 H.sub.37                                                                      hydroxyethylpiperazino                                        C.sub.12 H.sub.25                                                                    C.sub.12 H.sub.25                                                                      hydroxyethylpiperazino                                        C.sub.18 H.sub.37                                                                    CH.sub.3 hydroxyethylpiperazino                                        C.sub.18 H.sub.37                                                                    C.sub.18 H.sub.37                                                                      piperazino                                                    C.sub.12 H.sub.25                                                                    C.sub.12 H.sub.25                                                                      piperazino                                                    C.sub.18 H.sub.37                                                                    CH.sub.3 piperazino                                                     ##STR44##                                                                     R°                                                                            R'        R"         Z                                                ______________________________________                                        3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                     H        piperidino                                          3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                     H        morpholino                                          3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                     H        piperazino                                          4-OC.sub.18 H.sub.37                                                                 H         H        piperazino                                          4-OC.sub.18 H.sub.37                                                                 H         H        morpholino                                          4-OC.sub.18 H.sub.37                                                                 H         H        N-methylpiperazino                                  4-OC.sub.18 H.sub.37                                                                 2-CH.sub.3                                                                              6-CH.sub.3                                                                             N-methylpiperazino                                  4-OC.sub.18 H.sub.37                                                                 2-CH.sub.3                                                                              6-CH.sub.3                                                                             N-butylpiperazino                                   3,4-OCH.sub.2O                                                                             H        morpholino                                              3,4-OCH.sub.2O                                                                             H        N-(2-hydroxyethyl)piperazino                            4-OC.sub.8 H.sub.17                                                                  H         H        N-(2-hydroxyethyl)piperazino                        2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                            N-(2-hydroxyethyl)piperazino                        2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                            piperidino                                          2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                            N-isopropylpiperazino                               ______________________________________                                    

EXAMPLE XXIN,N-Dioctadecyl-N',N'-bis(2-Hydroxyethyl)-1,3-Propanediamine-N,N'-Dioxide

To a solution ofN,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine (3.34 g., 5mM.) in chloroform (20 ml.) is added m-chloroperbenzoic acid (2.76 g.,12 mM. of 86 percent material) in chloroform (20 ml.) dropwise. Thetemperature is maintained at 28° C. throughout the addition and for 1.5hours thereafter. The mixture is then diluted with chloroform (20 ml.)and the solution washed first with 1 N aqueous sodium hydroxide thenwith brine. It is then dried (Na₂ SO₄) and concentrated to an oil (2.5g.).

The hydrochloride salt is prepared by the procedure of Example V; m.p.89°-94° C., 114° C. (1.65 g. from 2.5 g. of oil).

Dissolution of the hydrochloride salt in chloroform and neutralizationwith aqueous sodium hydroxide regenerates the free base. It is recoveredby drying the chloroform layer (Na₂ SO₄) and evaporation of the solvent.Recrystallization from chloroform-ethylacetate provides the pure base;m.p. 95°-99° C.

The products of the preceding examples are converted to their N-oxidederivatives in like manner.

EXAMPLE XXIIN,N-Dioctadecyl-N',N'-bis(2-Hydroxyethyl)-1,3-Propanediamine N-MethoniumIodide

Methyl iodide (568 mg., 4.0 mM.) is added all at once to a solution ofN,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine (1.334 g.,2.0 mM) in methylene chloride (10 ml.) which is cooled in an ice-bath.The mixture is stirred and allowed over a four-hour period to warm toroom temperature, then stirred at room temperature overnight. The solidresidue obtained by removal of the chloroform is recrystallized fromethylacetate; 1.35 g., m.p. 120°-122° C.

EXAMPLE XXIII

Repetition of the procedures of Example III-B and C, but using theappropriate alkanediamine and acid chloride reactants provides thefollowing compounds:

    ______________________________________                                         ##STR45##                                                                     R.sub.1  R.sub.2   n       R.sub.3                                                                               R.sub.4                                   ______________________________________                                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        2      H       H                                          C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        2      C.sub.4 H.sub.9                                                                       H                                          C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3      H       (CH.sub.2).sub.4 OH                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3      CH.sub.3                                                                              (CH.sub.2).sub.4 OH                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3      H       (CH.sub.2).sub.5 OH                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3      C.sub.2 H.sub.5                                                                       (CH.sub.2).sub.5 OH                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        2      H       (CH.sub.2).sub.3 OH                        C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3      H       n-C.sub.3 H.sub.7                          C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3      H       n-C.sub.9 H.sub.19                         C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37                                                                        3      C.sub.2 H.sub.5                                                                       n-C.sub.9 H.sub.19                         ______________________________________                                    

example xxiv 1-dodecyl-4-(2-Hydroxyethyl)Piperazine

A solution of dodecylbromide (12.45 g., 0.05 mole) in ethanol (100 ml.)is added to a solution of 1-(2-hydroxyethyl)piperazine (6.5 g., 0.05mole) in ethanol (100 ml.) and the mixture stirred and refluxedovernight. Evaporation of the solvent gives the hydrobromide salt whichis recrystallized from acetone containing a small amount of ethanol. Thewhite crystalline salt melts at 99 degrees- 103 degrees C.

The free base is obtained by making an aqueous solution of thehydrobromide salt strongly alkaline with sodium hydroxide and extractingthe base with chloroform. The chloroform solution is washed with water,dried (Na₂ SO₄) and evaporated. The white solid which remains melts at65 degrees- 67 degrees C.

By means of the above procedure, the following compounds are preparedbut using the appropriate alkyl bromide and 1-(hydroxyalkyl)piperazinereactants:

    ______________________________________                                         ##STR46##                                                                     R.sub.8  p + 1     n       M.P. (degrees C.)                                 ______________________________________                                        C.sub.12 H.sub.25                                                                       3         0       55-7                                              C.sub.12 H.sub.25                                                                       3         0       95-8 (HBr salt)                                   C.sub.18 H.sub.37                                                                       2         0       108-10 (HBr salt)                                 C.sub.18 H.sub.37                                                                       3         0       111-12 (HBr salt)                                 C.sub.12 H.sub.25                                                                       6         0                                                         C.sub.20 H.sub.41                                                                       3         0                                                         C.sub.18 H.sub.37                                                                       5         0                                                         C.sub.18 H.sub.37                                                                       2         1                                                         C.sub.12 H.sub.25                                                                       3         2                                                         ______________________________________                                    

    ______________________________________                                         ##STR47##                                                                     r°                                                                               r'          r"        p + 1  n                                     ______________________________________                                        3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                       H          2      0                                     3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                       H          3      0                                     3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                       H          6      0                                     4-OC.sub.18 H.sub.37                                                                    2-CH.sub.3  6-CH.sub.3 3      0                                     4-OC.sub.18 H.sub.37                                                                    H           H          3      0                                     4-OC.sub.14 H.sub.29                                                                    H           H          5      0                                     3-OCH.sub.3                                                                             4-OC.sub.16 H.sub.33                                                                      H          2      0                                     4,5-OCH.sub.2O    2-C.sub.3 H.sub.7                                                                        5        0                                       2-OC.sub.2 H.sub.5                                                                      4-OC.sub.2 H.sub.5                                                                        5-C.sub.6 H.sub.13                                                                       3      0                                     3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                       H          2      1                                     4-OC.sub.18 H.sub.37                                                                    H           H          2      1                                     2-OCH.sub.3                                                                             4-OC.sub.18 H.sub.37                                                                      5-OCH.sub.3                                                                              2      1                                     2-OC.sub.16 H.sub.33                                                                    4-OC.sub.16 H.sub.33                                                                      5-OC.sub.16 H.sub.33                                                                     2      1                                     2-OC.sub.16 H.sub.33                                                                    4-OC.sub.16 H.sub.33                                                                      5-OC.sub.16 H.sub.33                                                                     2      2                                     3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                       H          2      2                                     3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                       H          3      2                                     4-OC.sub.18 H.sub.37                                                                    H           H          3      2                                     ______________________________________                                    

example xxvn,n-bis(3,4-Dihexoxybenzyl)-N',N'-Bis(2-Hydroxyethyl)-1,3-Propanediamine

A mixture of 3,4-dihexoxybenzaldehyde (15.3 g., 0.05 M), sodiumborohydride (1.85 g., 0.05 M) and ethanol (350 ml.) is stirred at roomtemperature for one hour and then concentrated in vacuo. The residue isdissolved in chloroform (500 ml.), the solution washed with water (4×100 ml.), dried (Na₂ SO₄) and evaporated under reduced pressure to give3,4-dihexoxybenzyl alcohol (15.0 g.) as a pale yellow oil.

Thionyl chloride (140 ml.) and 3,4-dihexoxybenzyl alcohol (14.0 g.) arecombined and stirred at room temperature for one-half hour, at whichtime gas evolution ceases. The mixture is refluxed for one-half hour andthen distilled to remove thionyl chloride (about 100 ml.). The residueis poured into ice-water (250 g. of each) and the aqueous solutionextracted with chloroform (3× 100 ml.). The chloroform extracts arecombined, washed successively with saturated sodium bicarbonate solution(2× 100 ml.) and water (3× 100 ml.). It is then dried (Na₂ SO₄) andconcentrated to give 3,4-dihexoxybenzyl chloride as a brown oil (11.7g.).

A mixture of N-(3-aminopropyl)diethanolamine (11.3 g., 7 mM),3,4-dihexoxybenzyl chloride (4.8 g., 15 mM) and potassium carbonate(2.07 g., 15 mM) is stirred at room temperature for 16 hours and then at130° C. for 2 hours. It is cooled, benzene (50 ml.) added and themixture filtered. The benzene filtrate is charged onto a column and thecolumn eluted with benzene (75 ml. fractions). The first elevenfractions collected are discarded. The column is then eluted withbenzene containing 10% ethanol. The second and third fractions arecollected, evaporated and the residue dissolved in methanol. Thedihydrochloride salt is prepared by bubbling hydrogen chloride into thesolution and then evaporating to a waxy solid (400 mg.).

In like manner, the followingN,N-bis(alkoxybenzyl)-N',N'-bis(2-hydroxyethyl)-1,3-propanediamines areprepared from appropriate reactants.

    ______________________________________                                         ##STR48##                                                                                                    Di-HCl                                         R'        R°  Base      M.P. (° C.)                            ______________________________________                                        H         4-C.sub.18 H.sub.37 O                                                                     --        >200                                          H         4-C.sub.12 H.sub.25 O                                                                     oil       --                                            H         4-C.sub.6 H.sub.13 O                                                                      oil       --                                            3-C.sub.12 H.sub.25 O                                                                   4-C.sub.12 H.sub.25 O                                                                     --        200-4                                         ______________________________________                                    

example xxvi n,n-bis(3,4-Dihexoxybenzyl)-1,3-Propanediamine

Raney nickel (500 mg.), 3,4-dihexoxybenzaldehyde (6.12, g., 0.02 M) andammonia (3.0 g., 0.177 M) in ethanol (100 ml.) are charged into a Paarshaker and hydrogenated at 40° C. and an initial pressure of 51 psi.When approximately 20 psi drop in hydrogen pressure is observed, about24 hours, the contents are removed and filtered. The filtrate isconcentrated in vacuo to an amber oil which is dissolved in ethylacetate (50 ml.). The solution is treated with ethyl acetate saturatedwith hydrogen chloride (100 ml.) and the resulting white hydrochloridesalt collected; 3.7 g., m.p. 205°-206° C. The salt is then partitionedbetween chloroform (100 ml.) and saturated sodium bicarbonate solution(50 ml.). The chloroform phase is separated, washed with water (50 ml.),dried (Na₂ SO₄) and concentrated to give 3,4-dihexoxybenzylamine as anoil; 3.2 g., 52.1% yield.

A solution of 3,4-dihexoxybenzylamine (2.0 g., 6.52 mM),3,4-dihexoxybenzaldehyde (2.0 g., 6.52 mM), benzene (75 ml.) andp-toluenesulfonic acid (200 mg.) is refluxed with stirring in apparatusequipped with a Dean-Stark collector for 16 hours. It is then cooled andconcentrated in vacuo to an oil which crystallizes upon standing: 4.0 g.of the Schiff base.

The Schiff base is reduced by treatment with sodium borohydride (0.378g.) in ethanol (50 ml. per 2.0 g. of Schiff base) at room temperaturefor 20 hours. The mixture is concentrated under reduced pressure to asolid which is taken up in methanol. Hydrogen chloride gas is bubbledinto the solution, water (50 ml.) added and the salt filtered, washedwith water and air dried. The dry salt is dissolved in warm methanol (75ml.), saturated aqueous sodium bicarbonate (50 ml.) and water (50 ml.)added. The solid is filtered off, washed with water and air dried. It isthen dissolved in chloroform (75 ml.), the solution washed with water(50 ml.), dried (Na₂ SO₄) and concentrated to givebis(3,4-dihexoxybenzyl)amine as an oil; 1.4 g., 69.8 % yield.

Acrylonitrile (15 ml.) and bis (3,4-dihexoxybenzyl)amine are refluxedtogether for 18 hours. The mixture is then cooled and concentrated invacuo to an oil: 1.2 g. 65 degrees- 67 degrees

The cyanoethyl derivative (1.2 g.), Raney nickel (500 mg.), ammonia (1.0g.) and ethanol (75 ml.) are charged into a Paar shaker and hydrogenatedat room temperature and an initial pressure of 50 psi. When uptake ofhydrogen is complete, the contents are removed, filtered andconcentrated to give the title product as an oil (1.02 g.).

The dihydrochloride salt is formed by dissolving the product in etherand bubbling hydrogen chloride into the solution. Removal of the etherunder reduced pressure gives the salt.

Similarly, N,N-bis(3,4-diisopropoxybenzyl)-1,3-propanediamine isprepared by substituting 3,4-diisopropoxybenzaldehyde for3,4-dihexoxybenzaldehyde. Its dihydrochloride salt melts at 65°-68° C.

EXAMPLE XXVII

The following N,N-bis (alkoxybenzyl)-α,ω-alkanediamine derivatives areprepared from appropriate reactants by the procedures of Examples XXV,XXVI and XI.

    __________________________________________________________________________     ##STR49##                                                                    R°                                                                             R'     R"     X      m  X'    R.sub.3  R.sub.4                        __________________________________________________________________________    2-OC.sub.3 H.sub.7                                                                    3-OC.sub.2 H.sub.5                                                                   H      --     0 CH.sub.2 CH.sub.2                                                                    CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           3-OCH.sub.3                                                                           4-OC.sub.16 H.sub.33                                                                 H      --     0 (CH.sub.2).sub.3                                                                     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           4-OC.sub.16 H.sub.33                                                                  H      H      --     0 (CH.sub.2).sub.4                                                                     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           3-OC.sub.12 H.sub.25                                                                  4-OC.sub.12 H.sub.25                                                                 H      --     0 (CH.sub.2).sub.3                                                                     C.sub.6 H.sub.13                                                                       C.sub.6 H.sub. 13              3-OC.sub.12 H.sub.25                                                                  4-OC.sub.12 H.sub.25                                                                 H      --     0 (CH.sub.2).sub.3                                                                     C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37              3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      --     0 (CH.sub.2).sub.6                                                                     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           4-OC.sub.18 H.sub.37                                                                  H      H      --     0 (CH.sub.2).sub.3                                                                     (CH.sub.2).sub.6 OH                                                                    (CH.sub.2).sub.6 OH            3-OCH.sub.3                                                                           4-OC.sub.16 H.sub.33                                                                 H      --     0 (CH.sub.2).sub.2                                                                     C.sub.20 H.sub.41                                                                      H                              2-OC.sub.2 H.sub.5                                                                    4-OC.sub.2 H.sub.5                                                                   5-C.sub.6 H.sub.13                                                                   --     0 (CH.sub.2).sub.6                                                                     C.sub.10 H.sub.21                                                                      C.sub.10 H.sub.21              4-OC.sub.8 H.sub.17                                                                   H      H      --     0 (CH.sub.2).sub.3                                                                     CH.sub.2CHCH.sub.2                                                                     CH.sub.2CHCH.sub.2             4-OC.sub.8 H.sub.17                                                                   H      H      CH.sub.2 CH.sub.2                                                                    1 CH.sub.2 CH.sub.2                                                                    CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           4-OC.sub.18 H.sub.37                                                                  H      H      (CH.sub.2).sub.3                                                                     1 (CH.sub.2 ).sub.3                                                                    CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      (CH.sub.2).sub.4                                                                     1 (CH.sub.2).sub.4                                                                     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           2-OC.sub.2 H.sub.5                                                                    4-OC.sub.2 H.sub.5                                                                   5-C.sub.2 H.sub.5                                                                    (CH.sub.2).sub.3                                                                     1 (CH.sub.2).sub.3                                                                     C.sub.18 H.sub.37                                                                      C.sub.18 H.sub.37              2-CH.sub.3                                                                            4-OC.sub.18 H.sub.37                                                                 6-CH.sub.3                                                                           CH.sub.2 CH.sub.2                                                                    1 CH.sub.2 CH.sub.2                                                                    (CH.sub.2).sub.4 OH                                                                    (CH.sub.2).sub.4 OH            2-OCH.sub.3                                                                           4-OC.sub.12 H.sub.25                                                                 6-OCH.sub.3                                                                          --     0 (CH.sub.2).sub.3                                                                     CH.sub.2 CHOHCH.sub.2 OH                                                               CH.sub.2 CHOHCH.sub.2 OH       4-OC.sub.12 H.sub.25                                                                  3-OC.sub.12 H.sub.25                                                                 H      --     0 (CH.sub.2).sub.3                                                                     CH.sub.2 CHOHCH.sub.2 OH                                                               CH.sub.2 CHOHCH.sub.2 OH       4-OC.sub.18 H.sub.37                                                                  H      H      --     0 (CH.sub.2).sub.3                                                                     H        C.sub.7 H.sub.15               3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      (CH.sub.2).sub.3                                                                     1  (CH.sub.2).sub.3                                                                    CH.sub.2 CHOHCH.sub.3                                                                  CH.sub.2 CHOHCH.sub.3          4-OC.sub.18 H.sub.37                                                                  2-CH.sub.3                                                                           6-CH.sub.3                                                                           --     0 (CH.sub.2).sub.3                                                                     CH.sub.2 COOCH.sub.3                                                                   CH.sub.2 COOCH.sub.3           4-OC.sub.16 H.sub.33                                                                  H      H      --     0 (CH.sub.2).sub.2                                                                     CH.sub.2 CH.sub.2 OC.sub.12                                                   H.sub.25 H                              2-O-i-C.sub.5 H.sub.11                                                                3-OC.sub.2 H.sub.5                                                                   H      (CH.sub.2).sub.2                                                                     1 (CH.sub.2).sub.2                                                                     C.sub.18 H.sub.37                                                                      CH.sub.2CHCH.sub.2             4-OC.sub.18 H.sub.37                                                                  H      H      (CH.sub.2).sub.2                                                                     1 (CH.sub.2).sub.2                                                                     CH.sub.2CHCH.sub.2                                                                     CH.sub.2CHCH.sub.2             3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      --     0 (CH.sub.2).sub.6                                                                     H        H                              4-OC.sub.18 H.sub.37                                                                  H      H      (CH.sub.2).sub.2                                                                     1 (CH.sub.2).sub.2                                                                     H        H                              2-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  5-OC.sub.6 H.sub.13                                                                  --     0 (CH.sub.2).sub.3                                                                     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           2-OCH.sub.3                                                                           4-OC.sub.18 H.sub.37                                                                 5-OCH.sub.3                                                                          --     0 (CH.sub.2).sub.4                                                                     C.sub.8 H.sub.17                                                                       C.sub.8 H.sub.17               2-OCH.sub.3                                                                           4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          --     0 (CH.sub.2).sub.3                                                                     H        H                              4-OC.sub.14 H.sub.29                                                                  H      H      --     0 (CH.sub.2).sub.2                                                                     H        H                              2-OC.sub.6 H.sub.13                                                                   3-OC.sub.2 H.sub.5                                                                   H      --     0 (CH.sub.2).sub.3                                                                     H        H                              3-OC.sub.12 H.sub.25                                                                  4-OC.sub.2 H.sub.5                                                                   H      --     0 (CH.sub.2).sub.6                                                                     H        H                              4-OC.sub.18 H.sub.37                                                                  H      H      --     0 (CH.sub.2).sub.3                                                                     H        H                              4-OC.sub.8 H.sub.17                                                                   H      H      --     0 (CH.sub.2).sub.3                                                                     H        H                              4-OC.sub.8 H.sub.17                                                                   H      H      --     0 (CH.sub.2).sub.3                                                                     CH.sub.2 CH(OCH.sub.3).sub.2                                                           CH.sub.2CHCH.sub.2             4-OC.sub.18 H.sub.37                                                                  2-CH.sub.3                                                                           6-CH.sub.3                                                                           --     0 (CH.sub.2).sub.3                                                                     H        H                              3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      CO     1 (CH.sub.2).sub.3                                                                     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           4-OC.sub.18 H.sub.37                                                                  H      H      CO     1 (CH.sub.2).sub.3                                                                     (CH.sub.2).sub.3 OH                                                                    (CH.sub.2).sub.3 OH            3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      CO     1 (CH.sub.2).sub.5                                                                     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           4,5-OCH.sub.2O 2-C.sub.3 H.sub.7                                                                    CO     1 (CH.sub.2).sub.6                                                                     (CH.sub.2).sub.8 OH                                                                    (CH.sub.2).sub.8 OH            4-OC.sub.14 H.sub.29                                                                  H      H      CO     1 (CH.sub.2).sub.3                                                                     CH.sub.2 CH.sub.2 OC.sub.4 H.sub.9                                                     CH.sub.2 CH.sub.2 OC.sub.4                                                    H.sub.9                        2-OC.sub.6 H.sub.13                                                                   3-OC.sub.2 H.sub.5                                                                   H      CO     1 (CH.sub.2).sub.3                                                                     CH.sub.2 COOCH.sub.3                                                                   CH.sub.2 COOCH.sub.3           4-OC.sub.8 H.sub.17                                                                   H      H      CO     1 (CH.sub.2).sub.3                                                                     CH.sub.2CHCH.sub.2                                                                     CH.sub.2CHCH.sub.2             3-OCH.sub.3                                                                           4-OC.sub.6 H.sub.13                                                                  5-OCH.sub.3                                                                          CO     1  (CH.sub.2).sub.3                                                                    CH.sub.2 COOC.sub.3 H.sub.7                                                            CH.sub.2 COOC.sub.3                                                           H.sub.7                        3-OC.sub.12 H.sub.25                                                                  4-OC.sub.12 H.sub.25                                                                 H      CO     1 (CH.sub.2).sub.3                                                                     (CH.sub.2).sub.6 OH                                                                    (CH.sub.2).sub.6 OH            4-OC.sub.8 H.sub.17                                                                   H      H      CO     1 (CH.sub.2).sub.3                                                                     CH.sub.2 CHOHCH.sub.3                                                                  CH.sub.2 CHOHCH.sub.3          4-OC.sub.8 H.sub.17                                                                   H      H      CO     1 (CH.sub.2).sub.5                                                                     (CH.sub.2).sub.3 OH                                                                    (CH.sub.2).sub.3 OH            4-OC.sub.8 H.sub.17                                                                   H      H      (CH.sub.2).sub.3                                                                     1 CO     CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH           4-OC.sub.8 H.sub.17                                                                   H      H      (CH.sub.2).sub.3                                                                     1 CO     C.sub.6 H.sub.13                                                                       C.sub.6 H.sub.13               4-OC.sub.14 H.sub.29                                                                  H      H      (CH.sub.2).sub.2                                                                     1 CO     CH.sub.2 CH.sub.2 OC.sub.4 H.sub.9                                                     CH.sub.2 CH.sub.2 OC.sub.4                                                    H.sub.9                        4-OC.sub.14 H.sub.29                                                                  H      H      (CH.sub.2).sub.2                                                                     1 CO     CH.sub.2CHCH.sub.2                                                                     CH.sub. 2CHCH.sub.2            4-OC.sub.18 H.sub.37                                                                  H      H      (CH.sub.2).sub.3                                                                     1 CO     CH.sub.2 COOCH.sub.3                                                                   CH.sub.2 COOCH.sub.3           3-OC.sub.12 H.sub.25                                                                  4-OC.sub.2 H.sub.5                                                                   H      (CH.sub.2).sub.6                                                                     1 CO     CH.sub.2 CHOHCH.sub.3                                                                  CH.sub.2 CHOHCH.sub.3          2-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  5-OC.sub.6 H.sub.13                                                                  (CH.sub.2).sub.3                                                                     1 CO     (CH.sub.2).sub.3 OH                                                                    (CH.sub.2).sub.3 OH            4-OC.sub.18 H.sub.37                                                                  H      H      --     0 (CH.sub.2).sub.2                                                                     CH.sub.2 CH.sub.2O                                                                     CH.sub.2 CH.sub.2              3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      --     0 (CH.sub.2).sub.2                                                                     CH.sub.2 CH.sub.2O                                                                     CH.sub.2 CH.sub.2              2-OCH.sub.3                                                                           4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          --     0 (CH.sub.2).sub.2                                                                     CH.sub.2 CH.sub.2O                                                                     CH.sub.2 CH.sub.2              3-OC.sub.6 H.sub.13                                                                   4-OC.sub.6 H.sub.13                                                                  H      --     0 3      CH.sub.2 CH.sub.2O                                                                     CH.sub.2 CH.sub.2              __________________________________________________________________________

the compounds of the above tabulation wherein R₃ and R₄ are hydroxyalkylgroups are converted to various derivatives by the procedures ofExamples VIII- X. In this manner, the hydroxy groups are converted to--OCH₂ CH₂ COOH, --OCONHC₆ H₅, --OCOCH₃ and --OCOC₁₅ H₃₁.

EXAMPLE XXVIII1-(Dioctadecylamino)methyl-4-[Bis-(2-Hydroxyethyl)Aminomethyl]Benzene

Dioctadecylamine (26.0 g., 0.05 M), α-bromo-p-tolunitrile (4.9 g., 0.025M) and chloroform (500 ml.) are stirred at room temperature for 24hours. The precipitate of dioctadecylamine hydrobromide is filtered offand the filtrate concentrated under reduced pressure. The residue isslurried in methanol, filtered, and evaporated to give1-(dioctadecylamino)methyl-4-cyanobenzene (15.5 g., 97.5% yield).

The nitrile (15 g.), ethylene dichoride (200 ml.), methanol (50 ml.) andwater (20 ml.) are combined and stirred at room temperature. Hydrogenchloride gas is bubbled into the mixture for three hours after which theyellow solution is refluxed for three hours. Methanol (50 ml.) and water(10 ml.) are added and hydrogen chloride bubbled into the mixture forone hour and refluxing continued for 14 hours. Methanol (10 ml.) andwater (2 ml.) are added and hydrogen chloride bubbled in for one hour.The mixture is refluxed for four hours, cooled to room temperature andmade alkaline by addition of saturated aqueous sodium bicarbonatesolution. The ethylene dichloride phase is separated and the aqueousphase extracted with chloroform (2× 100 ml.). The combined organicsolutions are washed with water (100 ml.), dried (Na₂ SO₄) andevaporated to give 1-(dioctadecylamino)methyl-4-carbomethoxy benzene(14.0 g., 73.6% yield).

A mixture of the thus produced ester (12.5 g., 18.7 mM), sodium dihydrobis-(2-methoxyethoxy)aluminate (11.0 g. of 70% reagent, 37.5 mM) andbenzene (300 ml.) is stirred at reflux for 24 hours. The mixture iscooled, aqueous sodium hydroxide (50 ml. of 10% solution) added and themixture thoroughly stirred. The benzene layer is separated, washed withwater (100 ml.), dried (Na₂ SO₄) and concentrated in vacuo to give thecorresponding alcohol as a semi-solid (9.68 g., 80.8%).

Thionyl chloride (90 ml.) and the alcohol produced above (9.6 g.) aremixed and refluxed for one hour. The mixture is poured into ice-water(150 g. each of ice and water) and the precipitate which forms filteredoff. It is dissolved in chloroform, the solution washed with saturatedaqueous sodium carbonate until the wash had pH 8.0, and then with water(2× 100 ml.). It is dried (Na₂ SO₄) and concentrated to give1-(dioctadecylamino)methyl-4-chloromethyl benzene as an amber oil (8.3g.). The residue is taken up in benzene and purified by chromatographyon silica gel using benzene, benzene 10% ethanol, ethanol, andethanol-methanol as successive eluents. The ethanol and ethanol-methanoleluates are combined and concentrated to give 4.58 g. of product

A solution of the chloromethyl compound (2.1 g., 3.2 mM), diethanolamine(1.3 g., 12.8 mM), and ethanol (50 ml.) is stirred at reflux for 18hours. It is cooled and concentrated in vacuo to an oil. The oil istaken up in chloroform (50 ml.), the solution washed with water (2× 50ml.), dried with anhydrous sodium sulfate and evaporated to an oil, 2.3g. It is purified by adsorption on a dry column of silica gel andelution with ethyl acetate. Concentration gives the title compound as asolid; 0.44 g., m.p. 49°-50° C.

In like manner, but using 2-amino-2-(hydroxymethyl)-1,3-propanediol inplace of diethanolamine produces1-(dioctadecylamino)methyl-4-[2-(2-hydroxymethyl)-1,3-dihydroxypropylaminomethyl]benzene.

Repetition of this procedure but using didodecylamine in place ofdioctadecylamine produces1-(didodecylamino)methyl-4-[bis(2-hydroxyethyl)-amino methyl]benzene.Its dihydrochloride salt prepared according to the procedure of ExampleXXV melts at 199°-204° C.

EXAMPLE XXIX

The following compounds are prepared from appropriate reactants by theprocedure of Example XXVIII. The column headed "Isomer" refers to thephenylenedimethylene moiety substituents.

    __________________________________________________________________________     ##STR50##                                                                    Isomer                                                                             R.sub.1                                                                            R.sub.2                                                                              R.sub.3      R.sub.4                                         __________________________________________________________________________    1,3  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2 CH.sub.2 OH                                                                       CH.sub.2 CH.sub.2 OH                              1,2  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2 CH.sub.2 OH                                                                       CH.sub.2 CH.sub.2 OH                              1,3  C.sub.12 H.sub.25                                                                  C.sub.12 H.sub.25                                                                  CH.sub.2 CH.sub.2 OH                                                                       CH.sub.2 CH.sub.2 OH                              1,2  C.sub.12 H.sub.25                                                                  C.sub.12 H.sub.25                                                                  CH.sub.2 CH.sub.2 OH                                                                       CH.sub.2 CH.sub.2 OH                              1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  (CH.sub.2).sub.3 OH                                                                        (CH.sub.2).sub.3 OH                               1,4  CH.sub.3                                                                           C.sub.12 H.sub.25                                                                  C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                   1,3  C.sub.16 H.sub.33                                                                  C.sub.16 H.sub.33                                                                  C.sub.6 H.sub. 13                                                                          C.sub.6 H.sub.13                                  1,2  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2 CHOHCH.sub.3                                                                      CH.sub.2 CHOHCH.sub.3                             1,4  n-C.sub.4 H.sub.9                                                                  C.sub.16 H.sub.33                                                                  (CH.sub.2).sub.8 OH                                                                        (CH.sub.2).sub.8 OH                               1,3  C.sub.16 H.sub.33                                                                  C.sub.16 H.sub.33                                                                  CH.sub.2 CH.sub.2 OH                                                                       CH.sub.2 CH.sub.2 OH                              1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2CHCH.sub.2                                                                         CH.sub.2CHCH.sub.2                                1,3  C.sub.2 H.sub.5                                                                    C.sub.20 H.sub.41                                                                  CH.sub.2CHCH.sub.2                                                                         CH.sub.2 CH.sub.2 OH                              1,3  C.sub.2 H.sub.5                                                                    C.sub.14 H.sub.29                                                                  C.sub.12 H.sub.25                                                                          C.sub.12 H.sub.25                                 1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2 CH(OCH.sub.3).sub.2                                                               CH.sub.2CHCH.sub.2                                1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  H            CH.sub.2 CHOHCH.sub.2 OH                          1,3  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  H            n-C.sub.7 H.sub.15                                1,3  C.sub.16 H.sub.33                                                                  C.sub.16 H.sub.33                                                                  H            CH(CH.sub.3)CH.sub.2 COOC.sub.2 H.sub.5           1,3  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2 COOCH.sub.3                                                                       CH.sub.2 COOCH.sub. 3                             1,3  C.sub.12 H.sub.25                                                                  C.sub.12 H.sub.25                                                                  (CH.sub.2).sub.2 OCOCH.sub.2 CH.sub.2 COOH                                                 (CH.sub.2).sub.2 OCOCH.sub.2 CH.sub.2 COOH*       1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  (CH.sub.2).sub.2 OCOCH.sub.2 CH.sub.2 COOH                                                 (CH.sub.2).sub.2 OCOCH.sub.2 CH.sub.2 COOH        1,4  n-C.sub.4 H.sub.9                                                                  C.sub.16 H.sub.33                                                                  (CH.sub.2).sub.8 OCOCH.sub.2 CH.sub.2 COOH                                                 (CH.sub.2).sub.8 OCOCH.sub.2 CH.sub.2 COOH        1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  (CH.sub.2).sub.2 OCONHC.sub.6 H.sub.5                                                      (CH.sub.2).sub.2 OCONHC.sub.6 H.sub.5             1,3  C.sub.12 H.sub.25                                                                  C.sub.12 H.sub.25                                                                  (CH.sub.2).sub.2 OCONHC.sub.6 H.sub.5                                                      (CH.sub.2).sub.2 OCONHC.sub.6 H.sub.5             1,4  n-C.sub.4 H.sub.9                                                                  C.sub.16 H.sub.33                                                                  (CH.sub.2).sub.8 OCONHC.sub.6 H.sub.5                                                      (CH.sub.2).sub.8 OCONHC.sub.6 H.sub.5             1,3  C.sub.12 H.sub.25                                                                  C.sub.12 H.sub.25                                                                  (CH.sub.2).sub.2 OCOCH.sub.3                                                               (CH.sub.2).sub.2 OCOCH.sub.3                      1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  (CH.sub.2).sub.2 OCOCH.sub.3                                                               (CH.sub.2).sub.2 OCOCH.sub.3                      1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  (CH.sub.2).sub.2 OCOC.sub.17 H.sub.35                                                      (CH.sub.2).sub.2 OCOC.sub.17 H.sub.35             1,3  C.sub.12 H.sub.25                                                                  C.sub.12 H.sub.25                                                                  (CH.sub.2).sub.2 OCOC.sub.5 H.sub.11                                                       (CH.sub.2).sub.2 OCOC.sub.5 H.sub.11              1,4  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2 CH.sub.2O                                                                         CH.sub.2 CH.sub.2                                 1,3  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  CH.sub.2 CH.sub.2O                                                                         CH.sub.2 CH.sub.2                                 1,4  n-C.sub.4 H.sub.9                                                                  C.sub.16 H.sub.33                                                                  CH.sub.2 CH.sub.2O                                                                         CH.sub.2 CH.sub.2                                 1,3  C.sub.18 H.sub.57                                                                  C.sub.18 H.sub.37                                                                  H            C.sub.2 H.sub.5                                   1,3  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  H            n-C.sub.3 H.sub.7                                 1,3  C.sub.18 H.sub.37                                                                  C.sub.18 H.sub.37                                                                  H            CH.sub.3                                          1,3  C.sub.16 H.sub.33                                                                  C.sub.16 H.sub.33                                                                  H            C.sub.2 H.sub.5                                   __________________________________________________________________________     *This compound and the remaining compounds are prepared from the              corresponding hydroxyalkyl compound by the procedures of Examples VIII -      X.                                                                       

EXAMPLE XXX 1-(Dioctadecyl)Aminomethyl-4-Aminomethyl Benzene

A mixture of 1-(dioctadecylamino)methyl-4-cyanobenzene (11.9 g., 18.7mM, see Example XXIX), sodium dihydro bis-(2-methoxyethoxy)aluminate(11.0 g. of 70% reagent, 37.5 mM) and benzene (300 ml.) under anatmosphere of nitrogen is refluxed for 40 hours. It is cooled andaqueous sodium hydroxide (50 ml. of 10% solution) is continuously added.The benzene phase is separated, washed with water (2× 50 ml.) and dried(Na₂ SO₄). Concentration of the benzene solution gives the product as anoil which solidifies on standing (8.0 g.). It is purified bychromatography on a dry silica gel column and elution with ethylacetate.

The dihydrochloride salt is obtained by dissolving the product (500 mg.)in chloroform (2 ml.) and adding ethyl acetate saturated with HCl (10ml.). The salt is filtered, washed with ether, and air dried: 430 mg.,m.p. 208°-210° C.

The following compounds are prepared in like manner from appropriatereactants:

    ______________________________________                                         ##STR51##                                                                                                          Di-HCl                                  Isomer*                                                                               R.sub.1      R.sub.2   Base   M.P. (° C.)                      ______________________________________                                        1,3-  C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          --     117-8                                   1,2-  C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                          --     90-2                                    1,4-  C.sub.12 H.sub.25                                                                         C.sub.12 H.sub.25                                                                          --     218-20                                  1,4-  3,4-dihexoxy-                                                                             3,4-dihexoxy-                                                                              oil    --                                            benzyl      benzyl                                                      1,4-  3,4-diisopro-                                                                             3,4-diisopro-                                                                              --     218-20                                        poxybenzyl  poxybenzyl                                                  ______________________________________                                         *Refers to position of the aminomethyl groups.                           

The compounds below are prepared by following the above procedure fromthe appropriate 1-(substituted amino)methyl cyanobenzenes prepared asintermediates in Example XXIX and from appropriate di(substitutedbenzyl)-amines prepared for Examples XXVI and XXVII.

    ______________________________________                                         ##STR52##                                                                    Isomer      R.sub.1        R.sub.2                                            ______________________________________                                        1,4         CH.sub.3       C.sub.12 H.sub.25                                  1,4         n-C.sub.4 H.sub.9                                                                            C.sub.16 H.sub.33                                  1,3         C.sub.2 H.sub.5                                                                              C.sub.20 H.sub.41                                  1,3         C.sub.2 H.sub.5                                                                              C.sub.14 H.sub.29                                  1,3         C.sub.14 H.sub.29                                                                            C.sub.18 H.sub.37                                  1,3         C.sub.16 H.sub.33                                                                            C.sub.18 H.sub.37                                  ______________________________________                                    

also those compounds in which ##STR53## may be prepared.

    ______________________________________                                        Isomer R°     R'            R"                                         ______________________________________                                        1,3    3-OC.sub.6 H.sub.13                                                                         4-OC.sub.6 H.sub.13                                                                         H                                          1,2    3-OC.sub.6 H.sub.13                                                                         4-OC.sub.6 H.sub.13                                                                         H                                          1,4    4-OC.sub.18 H.sub.37                                                                        H             H                                          1,3    4-OC.sub.18 H.sub.37                                                                        H             H                                          1,2    4-OC.sub.18 H.sub.37                                                                        H             H                                          1,3    4-OC.sub.14 H.sub.29                                                                        H             H                                          1,4    2-OCH.sub.3   4-OC.sub.12 H.sub.25                                                                        5-OCH.sub.3                                1,3    2-OCH.sub.3   4-OC.sub.12 H.sub.25                                                                        5-OCH.sub.3                                1,3    2-OC.sub.6 H.sub.12                                                                         3-OC.sub.2 H.sub.5                                                                          H                                          1,4    4-OC.sub.8 H.sub.17                                                                         H             H                                          1,3    3-OC.sub.12 H.sub.25                                                                        4-OC.sub.12 H.sub.25                                                                        H                                          1,3    4-OC.sub.18 H.sub.37                                                                        2-CH.sub.3    6-CH.sub.3                                 ______________________________________                                    

The above products are converted to monoacyl derivatives by theprocedure of Example III. By this procedure, the formyl, acetyl andpropionyl derivatives are obtained.

EXAMPLE XXXI 1-(Dihexadecyl)Aminomethyl-3-Aminomethyl Benzene

In a three-neck round bottom flask was placed wet Raney nickel (15 g.)in benzene (100 ml.). The slurry was refluxed and the water (9 ml.)collected in a Dean-Stark trap. The trap was removed and hexadecylamine(24.1 g.) in benzene (40 ml.) was added dropwise while refluxing. Afterthe addition was completed, the mixture was refluxed for sixteen hours.The mixture was then cooled, filtered through Super Cel on sinteredglass and evaporated to yield a white solid (24 g.). This solid wastwice recrystallized from a minimum amount (250 ml.) of hot acetone andwashed with cold acetone (40 ml.) to yield pure dihexadecylamine (18 g.,39% yield). Other preparations were done with yields as high as 73%.

To a N,N-dimethylacetamide (10 l.), which was dried over magnesiumsulfate and molecular seives, was added potassium carbonate (2960 g.)followed by dihexadecylamine (1000 g.) and α-bromomethyl-m-cyanobenzene(462 g.). This suspension was maintained at a temperature of 80°-90° C.on a steam bath for 1.5 hours until the reaction was substantiallycomplete as indicated by thin layer chromatography. The reaction mixturewas cooled to about 50° C. and decanted into ice (10 kg.). A lightyellow precipitate formed. The suspension was stirred for 15 minutes,filtered and the solids washed with cold water (12 l.). The filterfunnel containing the product was switched to a second filtration flaskand the solids were dissolved by washing twice with hexane (4 l. each).Impurities were hexane insoluble and remained in the funnel. The smallwater layer was decanted from the filtrate and the hexane solution driedover sodium sulfate (2,270 g.) and filtered through Super Cel. Thehexane solution was then reduced under vacuum to an oil which was thendissolved in a mixture of isopropyl alcohol and acetone (40:60, 10 l.).This mixture was then cooled to about 10°-15° C. and filtered throughSuper Cel. The filtrate was stirred and maintained at a temperature ofabout 5° C. until the formation of the white precipitate wassubstantially complete. The suspension was filtered cold and the solidrecrystallized again from said isopropyl alcohol/acetone solvent systemto yield the desired product, 1-(dihexadecyl)aminomethyl-3-cyanobenzene,mp 26°-27° C.

The ortho and para isomers of said product and also the ortho, meta andpara isomers of 1-(ditetradecyl), 1-(dieicosyl) and1-(dioctadecyl)aminomethyl cyanobenzene may be prepared by following theabove procedure.

1-(Dihexadecyl)aminomethyl-3-cyanobenzene (1,814 g.) was placed in anautoclave (15 gal.) with a mixture of hexane (1.98 l.), ethanol (17.82l.) and ammonia (3,627 g.). Said mixture was prepared in advance bysaturating the ethanol-hexane mixture with ammonia gas. The saturatedmixture was refrigerated until it was ready for use. Raney nickel (3,689g., wet weight) was added. The Raney nickel W2 is weighed as a wetslurry, the form in which it is obtained from W. R. Grace as Raneynickel No. 28. This differs from the standard W2 Raney nickel in that itis slurried in water rather than benzene. For the present process, thedifference is inconsequential. The mixture was contacted with hydrogengas maintained at a pressure of 50 psig. for four hours at roomtemperature. After the uptake of hydrogen ceased, the mixture wasfiltered and the filtrate concentrated to an oil by vacuum distillation.The oil was dissolved in methylene chloride (4.0 l.) and washed oncewith water (2.0 l.) and three times with a saturated sodium chloridesolution (1.0 l.). The clear methylene chloride solution was then driedover magnesium sulfate (454 g.), filtered and concentrated to an oilagain to yield 1-dihexadecyl)aminomethyl-3-aminomethylbenzene (1,236 g.,68% yield). The purity of the product was determined by thin layerchromatography. The dihydrochloride salt was prepared by dissolving the1-(dihexadecyl)aminomethyl-3-aminomethylbenzene (1,236 g.) in ethanol(5.0 l.) and ethanol (5.0 l.) containing dissolved hydrogen chloride gas(800 g.) was added. The mixture was stirred for one hour at roomtemperature and the solvent removed by vacuum distillation. Ether (8.0l.) was added to the residue until a clear solution was obtained.Cooling with a dry ice/acetone bath followed by the slow addition ofacetonitrile effected the precipitation of1-(dihexadecyl)aminomethyl-3-aminomethylbenzene diamine dihydrochlorideas a fine white crystalline material. The overall yield for the twoprocesses was 62.5%.

In a similar fashion the ortho and para isomers of said product and theortho, meta and para isomers of 1-(ditetradecyl), 1-diotacecyl) and1-(dieicosyl)aminomethyl-aminomethylbenzene may be prepared.

EXAMPLE XXXII

1-(substituted amino)methyl-4-hydroxymethyl benzene compounds preparedaccording to Examples XXV-XXIV are reacted with succinic anhydride,glutaric anhydride, phenyl isocyanate and acyl chlorides as described inExamples VIII, IX and X to give the following compounds:

    ______________________________________                                         ##STR54##                                                                    Isomer                                                                              R.sub.1     R.sub.2    A                                                ______________________________________                                        1,4   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOCH.sub.2 CH.sub.2 COOH                        1,3   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOCH.sub.2 CH.sub.2 COOH                        1,2   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOCH.sub.2 CH.sub.2 COOH                        1,3   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH               1,4   C.sub.12 H.sub.25                                                                         C.sub.12 H.sub.25                                                                        OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH               1,4   CH.sub.3    C.sub.6 H.sub.5 CH.sub.2                                                                 OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH               1,4   n-C.sub.4 H.sub.9                                                                         C.sub.16 H.sub.33                                                                        OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH               1,3   C.sub.6 H.sub.5 OCH.sub.2                                                                 C.sub.6 H.sub.5 OCH.sub.2                                                                OCOCH.sub.2 CH.sub.2 COOH                        1,2   C.sub.6 H.sub.13                                                                          C.sub.6 H.sub.13                                                                         OCOCH.sub.2 CH.sub.2 COOH                        1,3   C.sub.2 H.sub.5                                                                           C.sub.20 H.sub.41                                                                        OCOCH.sub.2 CH.sub.2 COOH                        1,4   CH.sub.2 CH.sub.2 OH                                                                      CH.sub.2 CH.sub. 2 OH                                                                    OCOCH.sub.2 CH.sub.2 COOH                        1,4   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCONHC.sub.6 H.sub.5                             1,3   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCONHC.sub.6 H.sub.5                             1,2   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCONHC.sub.6 H.sub.5                             1,4   CH.sub.3    C.sub.6 H.sub.5 CH.sub.2                                                                 OCONHC.sub.6 H.sub.5                             1,3   C.sub.6 H.sub.5 OCH.sub.2                                                                 C.sub.6 H.sub.5 OCH.sub.2                                                                OCONHC.sub.6 H.sub.5                             1,3   C.sub.16 H.sub.33                                                                         C.sub.16 H.sub.33                                                                        OCONHC.sub.6 H.sub.5                             1,4   n-C.sub.4 H.sub.9                                                                         C.sub.16 H.sub.33                                                                        OCONHC.sub.6 H.sub.5                             1,3   C.sub.2 H.sub.5                                                                           C.sub.20 H.sub.41                                                                        OCONHC.sub.6 H.sub.5                             1,3   C.sub.6 H.sub.5 CH.sub.2                                                                  C.sub.6 H.sub.5 CH.sub.2                                                                 OCONHC.sub.6 H.sub.5                             1,4   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOCH.sub.3                                      1,4   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOC.sub.7 H.sub.15                              1,4   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOC.sub.15 H.sub.31                             1,3   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOC.sub.15 H.sub.31                             1,2   C.sub.18 H.sub.37                                                                         C.sub.18 H.sub.37                                                                        OCOC.sub.3 H.sub.7                               1,4   C.sub.6 H.sub.13                                                                          C.sub.6 H.sub.13                                                                         OCOC.sub.5 H.sub.11                              1,3   C.sub.6 H.sub.5 OCH.sub.2                                                                 C.sub.6 H.sub.5 OCH.sub.2                                                                OCOC.sub.2 H.sub.5                               1,3   C.sub.6 H.sub.5 CH.sub.2                                                                  C.sub.6 H.sub.5 CH.sub.2                                                                 OCOC.sub.11 H.sub.23                             1,3   C.sub.2 H.sub.5                                                                           C.sub.20 H.sub.41                                                                        OCOCH.sub.3                                      1,4   CH.sub.3    C.sub.6 H.sub.5 CH.sub.2                                                                 OCOC.sub.17 H.sub.35                             1,4   C.sub.12 H.sub.25                                                                         C.sub.12 H.sub.25                                                                        OCOC.sub.7 H.sub.15                              1,2   C.sub.12 H.sub.25                                                                         C.sub.12 H.sub.25                                                                        OCOC.sub.7 H.sub.15                              ______________________________________                                    

example xxxiii

the compounds tabulated below are prepared by the procedures of ExamplesVIII, IX and X from appropriate 1-[bis-(alkoxy benzyl) aminomethyl]-4-hydroxymethyl benzenes. These latter compounds are preparedvia the procedures of Example XXVI ([bis(alkoxy benzyl)-amines]) andExample XXVIII ([1-bis(alkoxy benzyl)aminomethyl]-4-hydroxymethylbenzenes).

    __________________________________________________________________________     ##STR55##                                                                    Isomer                                                                             R°                                                                            R'     R"     A                                                   __________________________________________________________________________    1,4  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      OH                                                  1,4  3-O-i-C.sub.3 H.sub.7                                                                4-O-i-C.sub.3 H.sub.7                                                                H      OH                                                  1,3  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      OH                                                  1,4  4-OC.sub.18 H.sub.37                                                                 H      H      OH                                                  1,3  4-OC.sub.18 H.sub.37                                                                 H      H      OH                                                  1,2  4-OC.sub.18 H.sub.37                                                                 H      H      OH                                                  1,4  2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          OH                                                  1,2  2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          OH                                                  1,3  4-OC.sub.14 H.sub.29                                                                 H      H      OH                                                  1,2  2-OC.sub.6 H.sub.13                                                                  3-OC.sub.2 H.sub.5                                                                   H      OH                                                  1,3  3-OC.sub.12 H.sub.25                                                                 4-OC.sub.2 H.sub.5                                                                   H      OH                                                  1,3  4-OC.sub.8 H.sub.17                                                                  H      H      OH                                                  1,4  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      OCOCH.sub.2 CH.sub.2 COOH                           1,3  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      OCOCH.sub.2 CH.sub.2 COOH                           1,4  4-OC.sub.18 H.sub.37                                                                 H      H      OCOCH.sub.2 CH.sub.2 COOH                           1,3  4-OC.sub.18 H.sub.37                                                                 H      H      OCOCH.sub.2 CH.sub.2 COOH                           1,2  4-OC.sub.18 H.sub.37                                                                 H      H      OCOCH.sub.2 CH.sub.2 COOH                           1,2  2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          OCOCH.sub.2 CH.sub.2 COOH                           1,4  4-OC.sub.18 H.sub.37                                                                 H      H      OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH                  1,3  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH                  1,2  4-OC.sub.18 H.sub.37                                                                 H      H      OCOCH.sub.2 CH.sub.2 CH.sub.2 COOH                  1,4  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      OCONHC.sub.6 H.sub.5                                1,3  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      OCONHC.sub.6 H.sub.5                                1,4  4-OC.sub.18 H.sub.37                                                                 H      H      OCONHC.sub.6 H.sub.5                                1,2  4-OC.sub.18 H.sub.37                                                                 H      H      OCONHC.sub.6 H.sub.5                                1,2  2-OCH.sub.3                                                                          4-OCH.sub.12 H.sub.25                                                                5-OCH.sub.3                                                                          OCONHC.sub.6 H.sub.5                                1,3  4-OC.sub.8 H.sub.17                                                                  H      H      OCONHC.sub.6 H.sub.5                                1,4  3-O-i-C.sub.3 H.sub.7                                                                4-O-i-C.sub.3 H.sub.7                                                                H      OCONHC.sub.6 H.sub.5                                1,4  4-OC.sub.18 H.sub.37                                                                 H      H      OCOCH.sub.3                                         1,3  4-OC.sub.18 H.sub.37                                                                 H      H      OCOCH.sub.3                                         1,4  4-OC.sub.18 H.sub.37                                                                 H      H      OCOC.sub.7 H.sub.15                                 1,3  4-OC.sub.18 H.sub.37                                                                 H      H      OCOC.sub.15 H.sub.31                                1,4  4-OC.sub.8 H.sub.17                                                                  H      H      OCOC.sub.7 H.sub.15                                 1,2  4-OC.sub.18 H.sub.37                                                                 H      H      OCOC.sub.3 H.sub.7                                  1,2  2-OC.sub.6 H.sub.13                                                                  3-OC.sub.2 H.sub.5                                                                   H      OCOC.sub.9 H.sub.19                                 1,4  2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          OCOC.sub.17 H.sub.35                                1,4  4-OC.sub.18 H.sub.37                                                                 H      H      Cl                                                  1,4  4-OC.sub.8 H.sub.17                                                                  H      H      Cl                                                  1,3  4-OC.sub.18 H.sub.37                                                                 H      H      Cl                                                  1,3  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      Cl                                                  1,4  4-OC.sub.8 H.sub.17                                                                  H      H      Br                                                  1,2  2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          Br                                                  1,2  2-OC.sub.6 H.sub.13                                                                  3-OC.sub.2 H.sub.5                                                                   H      Br                                                  1,4  3-OC.sub.6 H.sub.13                                                                  4-OC.sub.6 H.sub.13                                                                  H      Cl                                                  1,4  3-O-i-C.sub.3 H.sub.7                                                                4-O-i-C.sub.3 H.sub.7                                                                H      Cl                                                  1,2  4-OC.sub.18 H.sub.37                                                                 H      H      Cl                                                  1,4  2-OCH.sub.3                                                                          4-OC.sub.12 H.sub.25                                                                 5-OCH.sub.3                                                                          Br                                                  1,3  4-OC.sub.14 H.sub.29                                                                 H      H      Br                                                  1,3  3-OC.sub.12 H.sub.25                                                                 4-OC.sub.2 H.sub.5                                                                   H      Br                                                  1,3  4-OC.sub.8 H.sub.17                                                                  H      H      Cl                                                  __________________________________________________________________________

EXAMPLE XXXIV [1-Bis(Alkoxybenzyl)Aminomethyl]-Alkylthiomethyl Benzenes

A solution of the appropriate[1-bis(alkoxybenzyl)aminomethyl]-chloromethyl (or bromomethyl) benzene(Example XXXIV) in N,N-dimethylformamide and at least one equivalent ofthe appropriate sodium alkylsulfide (prepared from the appropriatemercaptan and sodium hydride) is stirred for 16-60 hours at 40°-60° C.The mixture is diluted with four volumes of water and extracted withhexane. The extract is dried (Na₂ SO₄) and evaporated to give the crudeproduct. Purification is achieved by column chromatography on silicagel. The charged column is eluted first with benzene to remove unreactedstarting material and then with ethyl acetate or methanol to elute theproduct which is recovered by evaporation of the eluate.

The following compounds are thus prepared:

    __________________________________________________________________________     ##STR56##                                                                    Isomer                                                                             R° R'        R"    alkyl                                          __________________________________________________________________________    1,4  4-OC.sub.18 H.sub.37                                                                    H         H     CH.sub.3                                       1,4  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.6 H.sub.13                               1,4  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.18 H.sub.37                              1,3  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.6 H.sub.13                               1,3  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.18 H.sub.37                              1,3  4-OC.sub.18 H.sub.37                                                                    H         H     i-C.sub.3 H.sub.7                              1,2  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.6 H.sub.13                               1,4  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.12 H.sub.25                              1,3  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     C.sub.2 H.sub.5                                1,3  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     C.sub.12 H.sub.25                              1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub. 3                                                                        CH.sub.3                                       1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.4 H.sub.9                                1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.16 H.sub.33                              1,2  2-OC.sub.6 H.sub.13                                                                     3-OC.sub.2 H.sub.5                                                                      H     C.sub.2 H.sub.5                                1,2  2-OC.sub.6 H.sub.13                                                                     3-OC.sub.2 H.sub.5                                                                      H     C.sub.14 H.sub.29                              1,4  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     C.sub.12 H.sub.25                              1,4  3-O-i-C.sub.3 H.sub.7                                                                   4-O-i-C.sub.3 H.sub.7                                                                   H     i-C.sub.3 H.sub.7                              1,4  3-O-i-C.sub.3 H.sub.7                                                                   4-O-i-C.sub.3 H.sub.7                                                                   H     C.sub.12 H.sub.25                              1,4  3,4-OCH.sub.2O      H     C.sub.2 H.sub.5                                1,4  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.3 H.sub.7                                1,4  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.8 H.sub.17                               1,3  4-OC.sub.14 H.sub.29                                                                    4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.6 H.sub.13                               1,3  4-OC.sub.14 H.sub.29                                                                    4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.16 H.sub.33                              1,3  3-OC.sub.12 H.sub.25                                                                    4-OC.sub.2 H.sub.5                                                                      H     CH.sub.3                                       1,3  3-OC.sub.12 H.sub.25                                                                    4-OC.sub.2 H.sub.5                                                                      H     C.sub.10 H.sub. 21                             1,3  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.6 H.sub.13                               1,3  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.14 H.sub.29                              __________________________________________________________________________

example xxxv [1-bis(Alkoxybenzyl)Aminomethyl]-Alkoxymethyl Benzenes

The procedure of Examples XXXIV is repeated using the appropriate sodiumalkoxide in place of a sodium alkyl sulfide to give the followingcompounds:

    __________________________________________________________________________     ##STR57##                                                                    Isomer                                                                             R° R'        R"    alkyl                                          __________________________________________________________________________    1,4  4-OC.sub.18 H.sub.37                                                                    H         H     CH.sub.3                                       1,4  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.6 H.sub.13                               1,4  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.18 H.sub.37                              1,3  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.6 H.sub.13                               1,3  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.18 H.sub.37                              1,2  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.6 H.sub.13                               1,2  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.14 H.sub.29                              1,4  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.12 H.sub.25                              1,3  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     i-C.sub.3 H.sub.7                              1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         CH.sub.3                                       1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub. 6 H.sub.13                              1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.16 H.sub.33                              1,4  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     C.sub.6 H.sub.13                               1,4  3-O-i-C.sub.3 H.sub.7                                                                   4-O-i-C.sub.3 H.sub.7                                                                   H     C.sub.2 H.sub.5                                1,4  3-O-i-C.sub.3 H.sub.7                                                                   4-O-i-C.sub.3 H.sub.7                                                                   H     C.sub.14 H.sub.29                              1,3  4-OC.sub.14 H.sub.29                                                                    H         H     C.sub.4 H.sub.9                                1,4  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.3 H.sub.7                                1,4  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.10 H.sub.21                              1,3  3-OC.sub.12 H.sub.25                                                                    4-OC.sub.2 H.sub.5                                                                      H     CH.sub.3                                       1,3  3-OC.sub.12 H.sub.25                                                                    4-OC.sub.2 H.sub.5                                                                      H     C.sub.6 H.sub.13                               1,3  3-OC.sub.12 H.sub.25                                                                    4-OC.sub.2 H.sub.5                                                                      H     C.sub.16 H.sub.33                              1,3  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.6 H.sub.13                               __________________________________________________________________________

example xxxvi [1-bis(Alkoxybenzyl)Aminomethyl]-Cyanomethyl Benzenes

A solution of the appropriate [1-bis(alkoxybenzyl)aminomethyl]-chloro(or bromo) methyl benzene in N,N-dimethylformamide and potassiumcyanide-potassium iodide (5 equivalents of each) is stirred at 60°-100°C. for 24 hours. The mixture is diluted with water (4-5 volumes) andextracted with hexane. The extract is dried (Na₂ SO₄) and evaporated togive the crude product. It is purified by column chromatography as inExample XXXIV

In this manner the chloro and bromo compounds of Examples XXXIII areconverted to the corresponding cyano derivatives of the formula:##STR58##

EXAMPLE XXXVII [1-Bis(Alkoxybenzyl)Aminomethyl]-AlkanoylthiomethylBenzenes

A solution of equimolar amounts of the appropriate[1-bis-(alkoxybenzyl)aminomethyl]-chloro(or bromo)methylbenzene (ExampleXXXIII) and the sodium salt of the appropriate thiolcarboxylic acid inN,N-dimethylformamide is stirred for 16-20 hours at 60° C. The reactionmixture is cooled, diluted with 3-4 volumes of water and extracted withhexane. The extract is dried (Na₂ SO₄) and evaporated to give the crudeproduct. It is purified by column chromatography according to theprocedure of Example XXXIV.

The following compounds are thus prepared:

    __________________________________________________________________________     ##STR59##                                                                    Isomer                                                                             R° R'        R"    A"                                             __________________________________________________________________________    1,4  4-OC.sub.18 H.sub.37                                                                    H         H     CH.sub.3 CO                                    1,4  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.7 H.sub.15 CO                            1,3  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.11 H.sub.23 CO                           1,3  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     C.sub.2 H.sub.5 CO                             1,4  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.9 H.sub.19 CO                            1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.3 H.sub.7 CO                             1,2  2-OC.sub.6 H.sub.13                                                                     3-OC.sub.2 H.sub.5                                                                      H     C.sub.7 H.sub.15 CO                            1,4  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.17 H.sub.35 CO                           1,3  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     n-C.sub.4 H.sub.9 CO                           1,2  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.11 H.sub.23 CO                           1,3  4-OC.sub.8 H.sub.17                                                                     H         H     n-C.sub.4 H.sub.9 CO                           1,4  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     C.sub.16 H.sub.33 CO                           1,4  3-OC.sub.6 H.sub.13                                                                     4-OC.sub.6 H.sub.13                                                                     H     C.sub.3 H.sub.7 CO                             1,4  3-O-i-C.sub.3 H.sub.7                                                                   4-O-i-C.sub.3 H.sub.7                                                                   H     C.sub.11 H.sub.23 CO                           1,2  4-OC.sub.18 H.sub.37                                                                    H         H     C.sub.7 H.sub.15 CO                            1,4  2-OCH.sub.3                                                                             4-OC.sub.12 H.sub.25                                                                    5-OCH.sub.3                                                                         C.sub.9 H.sub.19 CO                            1,3  4-OC.sub.14 H.sub.29                                                                    H         H     C.sub.11 H.sub.23 CO                           1,3  3-OC.sub.12 H.sub.25                                                                    4-OC.sub.2 H.sub.5                                                                      H     C.sub.13 H.sub.27 CO                           1,3  4-OC.sub.8 H.sub.17                                                                     H         H     C.sub.13 H.sub.27 CO                           __________________________________________________________________________

what is claimed is:
 1. A compound of the structure ##STR60## or anon-toxic acid addition salt thereof wherein R₁ is alkyl of from 1 to 20carbon atoms;R₂ is alkyl of from 12 to 20 carbon atoms; R₃ is selectedfrom the group consisting of hydrogen and hydroxyalkyl of from 2 to 8carbon atoms; and R₄ is selected from the group consisting of hydrogen,alkyl of from 1 to 8 carbon atoms and hydroxyalkyl of from 2 to 8 carbonatoms.
 2. A compound of claim 1 wherein R₂ is alkyl of from 12 to 20carbon atoms.
 3. A compound of claim 2 wherein R₃ and R₄ are hydrogen.4. A compound of claim 2 wherein R₁ and R₂ are octadecyl, R₃ is hydrogenand R₄ is ethyl and the compound is the meta isomer.
 5. A compound ofclaim 2 wherein R₁ and R₂ are octadecyl, R₃ is hydrogen and R₄ is propyland the compound is the meta isomer.
 6. A compound of claim 2 wherein R₁and R₂ are octadecyl, R₃ is hydrogen and R₄ is methyl and the compoundis the meta isomer.
 7. A compound of claim 2 wherein R₁ and R₂ arehexadecyl, R₃ is hydrogen and R₄ is ethyl and the compound is the metaisomer.
 8. A compound of claim 2 wherein R₁ and R₂ are hexadecyl, R₃ andR₄ are 2-hydroxyethyl and the compound is the meta isomer.
 9. A compoundof claim 3 wherein R₁ and R₂ are octadecyl and the compound is the paraisomer.
 10. A compound of claim 3 wherein R₁ and R₂ are octadecyl andthe compound is the ortho isomer.
 11. A compound of claim 3 wherein R₁and R₂ are octadecyl and the compound is the meta isomer.
 12. A compoundof claim 3 wherein R₁ and R₂ are hexadecyl and the compound is the orthoisomer.
 13. A compound of claim 3 wherein R₁ and R₂ are hexadecyl andthe compound is the para isomer.
 14. A compound of claim 3 wherein R₁and R₂ are hexadecyl and the compound is the meta isomer.
 15. A compoundof claim 3 wherein R₁ is tetradecyl, R₂ is 16-methyl-n-heptadecyl andthe compound is the meta isomer.
 16. A compound of claim 3 wherein R₁and R₂ are eicosyl and the compound is the meta isomer.
 17. A compoundof claim 3 wherein R₁ is octadecyl, R₂ is hexadecyl and the compound isthe meta isomer.